{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Oncogene Addiction Hypothesis", "entry_form": "phenomenon", "gradeable_restatement": "Cancers with prospectively defined driver–tumor pairs depend on continuous dominant oncogene signaling for maintenance, so selective signaling withdrawal produces tumor regression.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Baseline driver mutation or amplification, tumor lineage, prior treatment and bulk-regression versus residual-cell endpoints fixed before response", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Oncogene Addiction Hypothesis", "central_claim": "Cancers with prospectively defined driver–tumor pairs depend on continuous dominant oncogene signaling for maintenance, so selective signaling withdrawal produces tumor regression.", "proposed_mechanism": "Cancers with prospectively defined driver–tumor pairs depend on continuous dominant oncogene signaling for maintenance, so selective signaling withdrawal produces tumor regression.", "claimed_scope": "Cancers with prospectively defined driver–tumor pairs depend on continuous dominant oncogene signaling for maintenance, so selective signaling withdrawal produces tumor regression.", "claimed_level": [ "maintenance" ], "is_conjunctive": true, "conjunctive_note": "Use the index specific-pair maintenance scope and separate most-cancer generalization. Baseline driver/tumor identity, treatment setting and endpoints define enrollment; responders are never used to define scope. Regression and elimination of residual disease are different outcomes." }, "rubric_routing": { "primary_rubric": "02-cancer-biology.md", "secondary_rubrics": [], "index_notes_applied": [ "Use the index specific-pair maintenance scope and separate most-cancer generalization. Baseline driver/tumor identity, treatment setting and endpoints define enrollment; responders are never used to define scope. Regression and elimination of residual disease are different outcomes." ], "rubric_fit_note": "Exact archived v5.3 framework. Any stale index empirical framing is rechecked against primary results." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "Selective withdrawal of dominant oncogene signaling regresses tumors in defined driver–cancer pairs.", "subclaim_type": "necessity", "scope": "baseline BCR-ABL/CML, EGFR/NSCLC, HER2/breast, BRAF/melanoma, ALK/NSCLC and genotype-defined experimental pairs", "claimed_scope": "baseline BCR-ABL/CML, EGFR/NSCLC, HER2/breast, BRAF/melanoma, ALK/NSCLC and genotype-defined experimental pairs", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Endogenous driver withdrawal/rescue, resistance alleles and molecularly enrolled trials", "hsef_level": "Η", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Η is supported for the prospectively named maintenance/regression pairs by endogenous conditional KRAS and MYC interventions, orthogonal EGFR withdrawal/drug controls, resistance alleles and several molecularly enrolled randomized trial families. This means causal regression in defined settings, not every enrolled tumor responding or every tumor cell requiring the driver. Nonresponse and context-specific bypass are major exceptions, preventing Θ and Ω." }, { "id": "SC2", "statement": "Most cancers depend on a single dominant oncogene in the same way.", "subclaim_type": "generalization", "scope": "prespecified pan-cancer lineages and baseline driver status", "claimed_scope": "prespecified pan-cancer lineages and baseline driver status", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Systematic functional dependency maps and independent tumor endpoints", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Experimental dual-driver and tissue comparisons, heterogeneous KRAS cell dependency and genome-wide resistance screens show context dependence. These reports do not constitute a representative native pan-cancer maintenance map establishing a single dominant dependency in most cancers. The broad model has mechanistic plausibility, but its prespecified denominator and matching causal test are missing." }, { "id": "SC3", "statement": "Driver withdrawal eliminates residual populations and gives durable treatment-free control.", "subclaim_type": "necessity", "scope": "baseline driver–tumor pair and residual-cell follow-up", "claimed_scope": "baseline driver–tumor pair and residual-cell follow-up", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Target-engaged stem/persister assays and withdrawal/rechallenge", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Initial regression and prolonged progression-free survival differ from eradication. Target-engaged human stem-cell survival, reversible tolerance, late resistance, transgene-independent recurrence and responder-selected treatment cessation contradict universal residual-cell elimination. Selected osteosarcoma differentiation or four-week off-treatment tumor absence after repeated Omomyc does not establish general lifelong cure." } ], "aggregation_rule": "scope-matched", "aggregation_preregistered": true, "aggregation_rationale": "Use the index specific-pair maintenance scope and separate most-cancer generalization. Baseline driver/tumor identity, treatment setting and endpoints define enrollment; responders are never used to define scope. Regression and elimination of residual disease are different outcomes.", "primary_subclaim_id": "SC1", "aggregation_derivation": "The preregistered scope-matched rule reports SC1 at Η: endogenous conditional-driver and common-conduit interventions, genetic withdrawal, mechanistic resistance/rescue and baseline molecularly defined clinical trials converge on tumor-maintenance dependence across named pairs. Significant primary nonresponse, host/apoptosis dependence and persistence prevent Θ or Ω. SC2 pan-cancer one-driver generalization and SC3 residual-cell eradication remain Γ as broader mechanistic claims without matching general causal validation.", "aggregation_alternatives": { "weakest_link_would_return": "Γ", "primary_subclaim_would_return": "Η", "scope_matched_would_return": "Η", "note": "Separate narrow successes do not replace the preregistered gate." }, "index_rule_deviation": "" }, "competing_models": { "models_evaluated": [ { "rank_in_tournament": 1, "model_id": "M1", "is_nominal": true, "name": "Scoped dominant-oncogene maintenance dependence", "core_claim": "A defined baseline driver can remain a rate-limiting maintenance node despite other genomic changes.", "explains_what_nominal_does_not": "A defined baseline driver can remain a rate-limiting maintenance node despite other genomic changes.", "strongest_supporting_evidence": [ "Endogenous conditional KRAS, endogenous MYC inhibition, EGFR genetic/drug controls and independent molecularly defined clinical trials converge (PMID22606359,18716624,16705038,12637609,20573926)." ], "strongest_contradictory_evidence": [ "This model explains bulk regression, not universal response, one-node pan-cancer maintenance or every residual cell." ], "hsef_level_for_this_model": "Η", "rationale": "Endogenous conditional KRAS, endogenous MYC inhibition, EGFR genetic/drug controls and independent molecularly defined clinical trials converge (PMID22606359,18716624,16705038,12637609,20573926). This model explains bulk regression, not universal response, one-node pan-cancer maintenance or every residual cell." }, { "rank_in_tournament": 2, "model_id": "M2", "is_nominal": false, "name": "Clonal bypass and lineage plasticity", "core_claim": "Selection restores drug-resistant target signaling or substitutes a different maintenance route.", "explains_what_nominal_does_not": "Selection restores drug-resistant target signaling or substitutes a different maintenance route.", "strongest_supporting_evidence": [ "Resistance-allele reconstruction and YAP gain/loss, binding-defective TEAD controls and orthotopic rescue discriminate true bypass from incomplete inhibition (PMID11423618,15737014,24954535)." ], "strongest_contradictory_evidence": [ "Serial biopsy association cannot identify every lineage mechanism; rtTA reactivation and functional bypass must remain distinct." ], "hsef_level_for_this_model": "Ζ", "rationale": "Resistance-allele reconstruction and YAP gain/loss, binding-defective TEAD controls and orthotopic rescue discriminate true bypass from incomplete inhibition (PMID11423618,15737014,24954535). Serial biopsy association cannot identify every lineage mechanism; rtTA reactivation and functional bypass must remain distinct." }, { "rank_in_tournament": 3, "model_id": "M4", "is_nominal": false, "name": "Reversible drug-tolerant state", "core_claim": "A reversibly altered cellular state survives treatment and can seed later resistance.", "explains_what_nominal_does_not": "A reversibly altered cellular state survives treatment and can seed later resistance.", "strongest_supporting_evidence": [ "Single-cell tolerance, independent barcode/kinetic route tests and GPX4 knockout with ferroptosis rescue and residual-xenograft course connect state survival to recurrence in bounded experimental settings (PMID20371346,26828195,29088702)." ], "strongest_contradictory_evidence": [ "Some sources share EGFR lines and investigator programmes; in vivo GPX4 tests remain xenografts. This is not all-patient endogenous proof or a clinical cure." ], "hsef_level_for_this_model": "Ζ", "rationale": "Single-cell tolerance, independent barcode/kinetic route tests and GPX4 knockout with ferroptosis rescue and residual-xenograft course connect state survival to recurrence in bounded experimental settings (PMID20371346,26828195,29088702). Some sources share EGFR lines and investigator programmes; in vivo GPX4 tests remain xenografts. This is not all-patient endogenous proof or a clinical cure." }, { "rank_in_tournament": 4, "model_id": "M3", "is_nominal": false, "name": "Non-addicted residual reservoir", "core_claim": "A residual compartment can survive strong signaling inhibition while the bulk regresses.", "explains_what_nominal_does_not": "A residual compartment can survive strong signaling inhibition while the bulk regresses.", "strongest_supporting_evidence": [ "Philadelphia-positive stem/progenitor survival with target engagement and cytokine controls, plus MYC liver dormancy, support the mechanism (PMID21157039,15475948)." ], "strongest_contradictory_evidence": [ "The decisive human evidence is ex vivo and does not selectively remove a lineage-proven native reservoir with matched rescue and relapse confirmation. Survival does not prove total BCR-ABL protein dispensability." ], "hsef_level_for_this_model": "Γ", "rationale": "Philadelphia-positive stem/progenitor survival with target engagement and cytokine controls, plus MYC liver dormancy, support the mechanism (PMID21157039,15475948). The decisive human evidence is ex vivo and does not selectively remove a lineage-proven native reservoir with matched rescue and relapse confirmation. Survival does not prove total BCR-ABL protein dispensability." }, { "rank_in_tournament": 5, "model_id": "M5", "is_nominal": false, "name": "Non-oncogene stress-support dependency", "core_claim": "Residual tumor states can acquire requirements for unmutated stress-support functions.", "explains_what_nominal_does_not": "Residual tumor states can acquire requirements for unmutated stress-support functions.", "strongest_supporting_evidence": [ "GPX4 loss and antioxidant rescue specifically kill persisters and block relapse in the tested residual melanoma xenograft (PMID29088702)." ], "strongest_contradictory_evidence": [ "A state-specific, genetically engineered xenograft dependency does not establish that stress support generally replaces mutated oncogenes as the dominant native cancer mechanism." ], "hsef_level_for_this_model": "Ε", "rationale": "GPX4 loss and antioxidant rescue specifically kill persisters and block relapse in the tested residual melanoma xenograft (PMID29088702). A state-specific, genetically engineered xenograft dependency does not establish that stress support generally replaces mutated oncogenes as the dominant native cancer mechanism." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. Politi paired genetic/drug and KRAS/placebo controls identify target-specific regression, while Corbin target-engaged survival and Kapoor verified YAP/TEAD bypass distinguish persistent or reassigned dependence from failed drug action (PMID16705038,21157039,24954535). The models are complementary at different times and compartments; ranking does not establish one universal cause.", "study_separating_rank1_from_rank2": "Politi paired genetic/drug and KRAS/placebo controls identify target-specific regression, while Corbin target-engaged survival and Kapoor verified YAP/TEAD bypass distinguish persistent or reassigned dependence from failed drug action (PMID16705038,21157039,24954535). The models are complementary at different times and compartments; ranking does not establish one universal cause.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "10488335", "title": "Reversible tumorigenesis by MYC in hematopoietic lineages.", "citation": "Felsher DW, Bishop JM et al. Reversible tumorigenesis by MYC in hematopoietic lineages. Molecular cell. 1999.", "doi": "10.1016/s1097-2765(00)80367-6", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/10488335/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/10488335/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID10488335", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "engineered autochthonous", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Conditional MYC in hematopoietic lineages yields tumors that regress after transgene inactivation.", "what_it_does_not_show": "Forced expression is not native human dosage; the abstract does not establish elimination of every residual cell or all sporadic tumors.", "confounders_present": [ "Forced expression is not native human dosage; the abstract does not establish elimination of every residual cell or all sporadic tumors." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Conditional MYC hematopoietic model programme." ] }, { "n": 2, "pmid": "10440378", "title": "Essential role for oncogenic Ras in tumour maintenance.", "citation": "Chin L, Tam A, Pomerantz J et al. Essential role for oncogenic Ras in tumour maintenance. Nature. 1999.", "doi": "10.1038/22788", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/10440378/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/10440378/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID10440378", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "engineered autochthonous", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Conditional H-RAS withdrawal regresses INK4a-null melanoma; enforced VEGF does not sustain the tumor after withdrawal.", "what_it_does_not_show": "Engineered induction and genotype constrain scope; vascular effects do not establish universal tumor dependence.", "confounders_present": [ "Engineered induction and genotype constrain scope; vascular effects do not establish universal tumor dependence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 3, "pmid": "10615128", "title": "Reversibility of acute B-cell leukaemia induced by BCR-ABL1.", "citation": "Huettner CS, Zhang P, Van Etten RA et al. Reversibility of acute B-cell leukaemia induced by BCR-ABL1. Nature genetics. 2000.", "doi": "10.1038/71691", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/10615128/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/10615128/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID10615128", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "engineered autochthonous", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Suppressing conditional BCR-ABL1 reverses acute B-cell leukemia, with repeated induction and remission cycles.", "what_it_does_not_show": "This mouse acute B-cell leukemia is not human chronic myeloid leukemia; repeat reversibility is not proven sterilization.", "confounders_present": [ "This mouse acute B-cell leukemia is not human chronic myeloid leukemia; repeat reversibility is not proven sterilization." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 4, "pmid": "12498714", "title": "Conditional activation of Neu in the mammary epithelium of transgenic mice results in reversible pulmonary metastasis.", "citation": "Moody SE, Sarkisian CJ, Hahn KT et al. Conditional activation of Neu in the mammary epithelium of transgenic mice results in reversible pulmonary metastasis. Cancer cell. 2002.", "doi": "10.1016/s1535-6108(02)00212-x", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/12498714/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/12498714/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID12498714", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "engineered autochthonous", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Neu withdrawal regresses mammary tumors and pulmonary metastases to undetectability, but most animals later recur with Neu-independent tumors.", "what_it_does_not_show": "Undetectable burden is not absence of residual cells; body controls were unavailable for examination.", "confounders_present": [ "Undetectable burden is not absence of residual cells; body controls were unavailable for examination." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Inducible Neu mammary model family." ] }, { "n": 5, "pmid": "16705038", "title": "Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors.", "citation": "Politi K, Zakowski MF, Fan PD et al. Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors. Genes & development. 2006.", "doi": "10.1101/gad.1417406", "pmcid": "PMC1475762", "url": "https://pubmed.ncbi.nlm.nih.gov/16705038/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16705038/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID16705038", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph22, 0:Publisher HTML paragraphs:paragraph23, 0:Publisher HTML paragraphs:paragraph24, 0:Publisher HTML paragraphs:paragraph34, 0:Publisher HTML paragraphs:paragraph36, 0:Publisher HTML paragraphs:paragraph45, 0:Publisher HTML paragraphs:paragraph47, 0:Publisher HTML paragraphs:paragraph50, 0:Publisher HTML paragraphs:paragraph64, 0:Publisher HTML paragraphs:paragraph73. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "engineered autochthonous", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Both EGFR transgene withdrawal and erlotinib during continued doxycycline regress mutant-EGFR tumors; placebo and KRAS tumors fail the drug response.", "what_it_does_not_show": "Transgene RNA is strongly induced and bulk protein is several-fold elevated; custom mouse MRI response and mostly normal histology do not establish eradication or physiological dosage.", "confounders_present": [ "Transgene RNA is strongly induced and bulk protein is several-fold elevated; custom mouse MRI response and mostly normal histology do not establish eradication or physiological dosage." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Inducible EGFR lung model family." ] }, { "n": 6, "pmid": "12098700", "title": "Sustained loss of a neoplastic phenotype by brief inactivation of MYC.", "citation": "Jain M, Arvanitis C, Chu K et al. Sustained loss of a neoplastic phenotype by brief inactivation of MYC. Science (New York, N.Y.). 2002.", "doi": "10.1126/science.1071489", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/12098700/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/12098700/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID12098700", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "engineered autochthonous", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Brief MYC withdrawal in osteosarcoma promotes differentiation and sustained loss of neoplastic behavior despite later reactivation.", "what_it_does_not_show": "This differentiation response is lineage specific and cannot establish treatment-free cure in every baseline driver pair.", "confounders_present": [ "This differentiation response is lineage specific and cannot establish treatment-free cure in every baseline driver pair." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 7, "pmid": "12517816", "title": "Genomically complex lymphomas undergo sustained tumor regression upon MYC inactivation unless they acquire novel chromosomal translocations.", "citation": "Karlsson A, Giuriato S, Tang F et al. Genomically complex lymphomas undergo sustained tumor regression upon MYC inactivation unless they acquire novel chromosomal translocations. Blood. 2003.", "doi": "10.1182/blood-2002-10-3091", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/12517816/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/12517816/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID12517816", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "engineered autochthonous", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Genomically complex MYC lymphomas often regress after MYC inactivation; some escape with further chromosomal changes.", "what_it_does_not_show": "The engineered lymphoma lineage and heterogeneous escape preclude universal dependence or cure.", "confounders_present": [ "The engineered lymphoma lineage and heterogeneous escape preclude universal dependence or cure." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Conditional MYC hematopoietic model programme." ] }, { "n": 8, "pmid": "15475948", "title": "MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer.", "citation": "Shachaf CM, Kopelman AM, Arvanitis C et al. MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature. 2004.", "doi": "10.1038/nature03043", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/15475948/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15475948/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID15475948", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "engineered autochthonous", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "MYC withdrawal in liver tumors induces differentiation and dormancy; reactivation restores neoplastic properties in genetically related cells.", "what_it_does_not_show": "Persistence is compatible with bulk addiction, and the abstract alone does not resolve every residual-cell dependency or reservoir-specific intervention.", "confounders_present": [ "Persistence is compatible with bulk addiction, and the abstract alone does not resolve every residual-cell dependency or reservoir-specific intervention." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 9, "pmid": "17056717", "title": "Sustained regression of tumors upon MYC inactivation requires p53 or thrombospondin-1 to reverse the angiogenic switch.", "citation": "Giuriato S, Ryeom S, Fan AC et al. Sustained regression of tumors upon MYC inactivation requires p53 or thrombospondin-1 to reverse the angiogenic switch. Proceedings of the National Academy of Sciences of the United States of America. 2006.", "doi": "10.1073/pnas.0608017103", "pmcid": "PMC1637571", "url": "https://pubmed.ncbi.nlm.nih.gov/17056717/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17056717/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID17056717", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "engineered autochthonous", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "p53 deficiency impairs sustained MYC-withdrawal regression; p53 or thrombospondin restoration restores the response in the studied setting.", "what_it_does_not_show": "Thrombospondin alone is insufficient; genotype and vascular mechanisms modify dependence rather than prove all-cancer withdrawal sufficiency.", "confounders_present": [ "Thrombospondin alone is insufficient; genotype and vascular mechanisms modify dependence rather than prove all-cancer withdrawal sufficiency." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Conditional MYC tumor/host programme." ] }, { "n": 10, "pmid": "21035406", "title": "CD4(+) T cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation.", "citation": "Rakhra K, Bachireddy P, Zabuawala T et al. CD4(+) T cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation. Cancer cell. 2010.", "doi": "10.1016/j.ccr.2010.10.002", "pmcid": "PMC2991103", "url": "https://pubmed.ncbi.nlm.nih.gov/21035406/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21035406/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID21035406", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "engineered autochthonous", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "CD4 immunity and thrombospondin contribute to sustained regression after MYC or BCR-ABL inactivation.", "what_it_does_not_show": "Host-dependent sustained control differs from immediate cell-autonomous collapse; linked erratum details were not examined.", "confounders_present": [ "Host-dependent sustained control differs from immediate cell-autonomous collapse; linked erratum details were not examined." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Conditional MYC/BCR-ABL tumor/host programme." ] }, { "n": 11, "pmid": "22232209", "title": "Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice.", "citation": "Collins MA, Bednar F, Zhang Y et al. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. The Journal of clinical investigation. 2012.", "doi": "10.1172/JCI59227", "pmcid": "PMC3266788", "url": "https://pubmed.ncbi.nlm.nih.gov/22232209/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22232209/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID22232209", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "engineered autochthonous", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Conditional oncogenic Kras withdrawal regresses pancreatic lesions and changes the associated stroma.", "what_it_does_not_show": "The engineered pancreas and p53 settings cannot establish all sporadic pancreatic tumors or residual-cell elimination.", "confounders_present": [ "The engineered pancreas and p53 settings cannot establish all sporadic pancreatic tumors or residual-cell elimination." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Conditional pancreatic Kras model programme." ] }, { "n": 12, "pmid": "22606359", "title": "Temporal dissection of K-ras(G12D) mutant in vitro and in vivo using a regulatable K-ras(G12D) mouse allele.", "citation": "Wang Z, Feng Y, Bardeesy N et al. Temporal dissection of K-ras(G12D) mutant in vitro and in vivo using a regulatable K-ras(G12D) mouse allele. PloS one. 2012.", "doi": "10.1371/journal.pone.0037308", "pmcid": "PMC3350485", "url": "https://pubmed.ncbi.nlm.nih.gov/22606359/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22606359/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID22606359", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Strong", "system": "endogenous conditional knock-in", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Switching off an endogenous conditional KRAS fusion allele regresses pancreatic tumors.", "what_it_does_not_show": "The switch remains an engineered fusion and genotype-specific test; a linked author-name correction does not add an independent causal experiment.", "confounders_present": [ "The switch remains an engineered fusion and genotype-specific test; a linked author-name correction does not add an independent causal experiment." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 13, "pmid": "18356293", "title": "Oncogene cooperation in tumor maintenance and tumor recurrence in mouse mammary tumors induced by Myc and mutant Kras.", "citation": "Podsypanina K, Politi K, Beverly LJ et al. Oncogene cooperation in tumor maintenance and tumor recurrence in mouse mammary tumors induced by Myc and mutant Kras. Proceedings of the National Academy of Sciences of the United States of America. 2008.", "doi": "10.1073/pnas.0801197105", "pmcid": "PMC2278195", "url": "https://pubmed.ncbi.nlm.nih.gov/18356293/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18356293/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID18356293", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "engineered autochthonous", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Dual MYC and KRAS mammary tumors regress more strongly when both are removed; recurrent tumors can reactivate inducible transgenes through rtTA mutations.", "what_it_does_not_show": "Reactivation is different from verified driver-independent bypass; the result contests one-node generalization rather than proving every recurrent mechanism.", "confounders_present": [ "Reactivation is different from verified driver-independent bypass; the result contests one-node generalization rather than proving every recurrent mechanism." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 14, "pmid": "18461184", "title": "Combined Inactivation of MYC and K-Ras oncogenes reverses tumorigenesis in lung adenocarcinomas and lymphomas.", "citation": "Tran PT, Fan AC, Bendapudi PK et al. Combined Inactivation of MYC and K-Ras oncogenes reverses tumorigenesis in lung adenocarcinomas and lymphomas. PloS one. 2008.", "doi": "10.1371/journal.pone.0002125", "pmcid": "PMC2365560", "url": "https://pubmed.ncbi.nlm.nih.gov/18461184/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18461184/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID18461184", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "engineered autochthonous", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "MYC and KRAS withdrawal effects differ between lung tumors and lymphomas; dual withdrawal exceeds MYC-only lung responses.", "what_it_does_not_show": "Cooperating pathways and tissue context preclude a uniform one-oncogene rule.", "confounders_present": [ "Cooperating pathways and tissue context preclude a uniform one-oncogene rule." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 15, "pmid": "23532334", "title": "PUMA and BIM are required for oncogene inactivation-induced apoptosis.", "citation": "Bean GR, Ganesan YT, Dong Y et al. PUMA and BIM are required for oncogene inactivation-induced apoptosis. Science signaling. 2013.", "doi": "10.1126/scisignal.2003483", "pmcid": "PMC3753585", "url": "https://pubmed.ncbi.nlm.nih.gov/23532334/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23532334/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID23532334", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph0, 1:RESULTS:paragraph1, 1:RESULTS:paragraph2, 1:RESULTS:paragraph6, 1:RESULTS:paragraph7, 1:RESULTS:paragraph8. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "engineered autochthonous", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "BIM or PUMA loss reduces apoptosis and slows HER2-withdrawal regression; PUMA loss also impairs EGFR-withdrawal lung regression. Constitutive AKT/MEK separates downstream apoptotic routes.", "what_it_does_not_show": "Apoptotic competence modifies response, and these inducible models do not show that every residual cell must depend on the driver.", "confounders_present": [ "Apoptotic competence modifies response, and these inducible models do not show that every residual cell must depend on the driver." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Inducible Neu and EGFR model families." ] }, { "n": 16, "pmid": "15095297", "title": "Reversible lymphomagenesis in conditionally c-MYC expressing mice.", "citation": "Marinkovic D, Marinkovic T, Mahr B et al. Reversible lymphomagenesis in conditionally c-MYC expressing mice. International journal of cancer. 2004.", "doi": "10.1002/ijc.20099", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/15095297/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15095297/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID15095297", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "engineered tumor lineage", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Fate-labeled MYC lymphoma cells undergo arrest, differentiation and apoptosis after MYC withdrawal.", "what_it_does_not_show": "A selected engineered lymphoma is not a representative pan-cancer dependency survey.", "confounders_present": [ "A selected engineered lymphoma is not a representative pan-cancer dependency survey." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 17, "pmid": "18716624", "title": "Modelling Myc inhibition as a cancer therapy.", "citation": "Soucek L, Whitfield J, Martins CP et al. Modelling Myc inhibition as a cancer therapy. Nature. 2008.", "doi": "10.1038/nature07260", "pmcid": "PMC4485609", "url": "https://pubmed.ncbi.nlm.nih.gov/18716624/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18716624/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "Omomyc-Kras", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "endogenous-driver autochthonous", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Omomyc inhibition of endogenous MYC regresses KRAS-driven lung tumors with reversible effects on normal regenerative tissues.", "what_it_does_not_show": "MYC is a downstream common conduit rather than the mutated initiating KRAS itself; later work shares the model family.", "confounders_present": [ "MYC is a downstream common conduit rather than the mutated initiating KRAS itself; later work shares the model family." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Omomyc/Kras autochthonous model family." ] }, { "n": 18, "pmid": "23475959", "title": "Inhibition of Myc family proteins eradicates KRas-driven lung cancer in mice.", "citation": "Soucek L, Whitfield JR, Sodir NM et al. Inhibition of Myc family proteins eradicates KRas-driven lung cancer in mice. Genes & development. 2013.", "doi": "10.1101/gad.205542.112", "pmcid": "PMC3605464", "url": "https://pubmed.ncbi.nlm.nih.gov/23475959/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23475959/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID42386384" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "Omomyc-Kras", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph14, 0:Publisher HTML paragraphs:paragraph15, 0:Publisher HTML paragraphs:paragraph18, 0:Publisher HTML paragraphs:paragraph19, 0:Publisher HTML paragraphs:paragraph20, 0:Publisher HTML paragraphs:paragraph25, 0:Publisher HTML paragraphs:paragraph28, 0:Publisher HTML paragraphs:paragraph32, 0:Publisher HTML paragraphs:paragraph34, 0:Publisher HTML paragraphs:paragraph35. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "endogenous-driver autochthonous", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Repeated four-week Omomyc on/off cycles lower KRAS-lung tumor recurrence; after eight cycles, three of four mice have no scored tumors after four weeks off. Refractory lesions suppress Omomyc expression.", "what_it_does_not_show": "All animals recur after a first cycle; the final off-treatment cohort is small, histology excludes atypical hyperplasia, and four weeks is not lifelong sterile eradication. Linked erratum details remain unexamined.", "confounders_present": [ "All animals recur after a first cycle; the final off-treatment cohort is small, histology excludes atypical hyperplasia, and four weeks is not lifelong sterile eradication. Linked erratum details remain unexamined." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Omomyc/Kras autochthonous model family." ] }, { "n": 19, "pmid": "19064915", "title": "A mouse model for EML4-ALK-positive lung cancer.", "citation": "Soda M, Takada S, Takeuchi K et al. A mouse model for EML4-ALK-positive lung cancer. Proceedings of the National Academy of Sciences of the United States of America. 2008.", "doi": "10.1073/pnas.0805381105", "pmcid": "PMC2605003", "url": "https://pubmed.ncbi.nlm.nih.gov/19064915/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19064915/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID19064915", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "engineered autochthonous", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Lung-specific transgenic EML4-ALK tumors respond to an ALK inhibitor in the experimental mouse setting.", "what_it_does_not_show": "Forced expression and transformation assays do not by themselves establish a native universal maintenance dependence.", "confounders_present": [ "Forced expression and transformation assays do not by themselves establish a native universal maintenance dependence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 20, "pmid": "17625570", "title": "Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.", "citation": "Soda M, Choi YL, Enomoto M et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007.", "doi": "10.1038/nature05945", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/17625570/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17625570/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID17625570", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell transformation and human specimens", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "EML4-ALK fusions are identified in human lung tumors and transform experimental cells.", "what_it_does_not_show": "Discovery and transformation capacity do not test continued native tumor maintenance.", "confounders_present": [ "Discovery and transformation capacity do not test continued native tumor maintenance." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 21, "pmid": "8616716", "title": "Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells.", "citation": "Druker BJ, Tamura S, Buchdunger E et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nature medicine. 1996.", "doi": "10.1038/nm0596-561", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/8616716/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/8616716/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID8616716", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human ex vivo", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "The selective ABL inhibitor suppresses CML colony formation while largely preserving normal hematopoietic growth.", "what_it_does_not_show": "Colony suppression is not elimination of quiescent leukemic stem cells or an in vivo maintenance intervention.", "confounders_present": [ "Colony suppression is not elimination of quiescent leukemic stem cells or an in vivo maintenance intervention." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 22, "pmid": "11287972", "title": "Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia.", "citation": "Druker BJ, Talpaz M, Resta DJ et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. The New England journal of medicine. 2001.", "doi": "10.1056/NEJM200104053441401", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/11287972/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/11287972/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID11287972", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "In phase 1 CML testing, 53 of 54 patients receiving at least 300 mg daily obtain complete hematologic response.", "what_it_does_not_show": "Dose-cohort selection, nonrandomization and hematologic response do not establish cure or an all-dose response.", "confounders_present": [ "Dose-cohort selection, nonrandomization and hematologic response do not establish cure or an all-dose response." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 23, "pmid": "12637609", "title": "Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia.", "citation": "O'Brien SG, Guilhot F, Larson RA et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. The New England journal of medicine. 2003.", "doi": "10.1056/NEJMoa022457", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/12637609/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/12637609/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID12637609", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "IRIS randomizes 1106 CML patients and shows better cytogenetic response and progression control with imatinib than interferon plus cytarabine.", "what_it_does_not_show": "Crossover complicates survival inference; drug treatment does not equal genetic removal or residual-cell eradication.", "confounders_present": [ "Crossover complicates survival inference; drug treatment does not equal genetic removal or residual-cell eradication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 24, "pmid": "15118073", "title": "Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.", "citation": "Lynch TJ, Bell DW, Sordella R et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. The New England journal of medicine. 2004.", "doi": "10.1056/NEJMoa040938", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/15118073/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15118073/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID15118073", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human specimens and cell perturbation", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "EGFR kinase mutations associate with gefitinib response and show functional inhibitor sensitivity.", "what_it_does_not_show": "The discovery comparison selects responders and nonresponders after outcome; it is not a prospective genotype-enrolled response denominator.", "confounders_present": [ "The discovery comparison selects responders and nonresponders after outcome; it is not a prospective genotype-enrolled response denominator." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 25, "pmid": "15329413", "title": "EGF receptor gene mutations are common in lung cancers from \"never smokers\" and are associated with sensitivity of tumors to gefitinib and erlotinib.", "citation": "Pao W, Miller V, Zakowski M et al. EGF receptor gene mutations are common in lung cancers from \"never smokers\" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proceedings of the National Academy of Sciences of the United States of America. 2004.", "doi": "10.1073/pnas.0405220101", "pmcid": "PMC516528", "url": "https://pubmed.ncbi.nlm.nih.gov/15329413/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15329413/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID15329413", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human specimens and cell perturbation", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "EGFR mutations associate with inhibitor-sensitive lung cancer and alter drug-sensitive phosphorylation in experimental systems.", "what_it_does_not_show": "Outcome-based discovery and smoking-history enrichment do not establish response in every prospectively defined mutation-positive tumor.", "confounders_present": [ "Outcome-based discovery and smoking-history enrichment do not establish response in every prospectively defined mutation-positive tumor." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 26, "pmid": "19692680", "title": "Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.", "citation": "Mok TS, Wu YL, Thongprasert S et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. The New England journal of medicine. 2009.", "doi": "10.1056/NEJMoa0810699", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/19692680/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19692680/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID19692680", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "In IPASS, gefitinib favors progression control in the mutation-positive subgroup and disadvantages mutation-negative patients relative to chemotherapy.", "what_it_does_not_show": "Enrollment uses clinical features rather than EGFR genotype, and the molecular analysis is a tested subsample; subgroup estimates are not the entire enrolled cohort.", "confounders_present": [ "Enrollment uses clinical features rather than EGFR genotype, and the molecular analysis is a tested subsample; subgroup estimates are not the entire enrolled cohort." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 27, "pmid": "20573926", "title": "Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR.", "citation": "Maemondo M, Inoue A, Kobayashi K et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. The New England journal of medicine. 2010.", "doi": "10.1056/NEJMoa0909530", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/20573926/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20573926/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID20573926", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Baseline EGFR-mutant NEJ002 enrollment yields 73.7 percent response and 10.8-month median progression-free survival with gefitinib, versus 30.7 percent and 5.4 months with chemotherapy.", "what_it_does_not_show": "Responses are not universal; reported overall-survival comparison is not statistically decisive, and recurrence remains compatible with bulk addiction.", "confounders_present": [ "Responses are not universal; reported overall-survival comparison is not statistically decisive, and recurrence remains compatible with bulk addiction." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 28, "pmid": "29151359", "title": "Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer.", "citation": "Soria JC, Ohe Y, Vansteenkiste J et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. The New England journal of medicine. 2018.", "doi": "10.1056/NEJMoa1713137", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/29151359/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29151359/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "FLAURA", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "FLAURA randomizes 556 baseline EGFR-mutant patients; osimertinib improves progression-free survival relative to active first-generation EGFR inhibitors.", "what_it_does_not_show": "Both arms inhibit the same driver, so this comparison does not isolate inhibition versus none; initial response is not eradication.", "confounders_present": [ "Both arms inhibit the same driver, so this comparison does not isolate inhibition versus none; initial response is not eradication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "FLAURA 556-patient trial." ] }, { "n": 29, "pmid": "31751012", "title": "Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC.", "citation": "Ramalingam SS, Vansteenkiste J, Planchard D et al. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. The New England journal of medicine. 2020.", "doi": "10.1056/NEJMoa1913662", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/31751012/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31751012/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "FLAURA", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Later FLAURA analysis reports median overall survival of 38.6 versus 31.8 months.", "what_it_does_not_show": "This is follow-up of the same 556-patient trial, not independent confirmation; survival benefit is not proof of sterile cure.", "confounders_present": [ "This is follow-up of the same 556-patient trial, not independent confirmation; survival benefit is not proof of sterile cure." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "FLAURA 556-patient trial follow-up." ] }, { "n": 30, "pmid": "11248153", "title": "Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.", "citation": "Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. The New England journal of medicine. 2001.", "doi": "10.1056/NEJM200103153441101", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/11248153/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/11248153/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID11248153", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "HER2-selected metastatic breast cancer shows greater response and longer survival with trastuzumab plus chemotherapy than chemotherapy alone.", "what_it_does_not_show": "Antibody-mediated immunity and chemotherapy contribute; this is not pure selective kinase withdrawal, and many tumors do not respond.", "confounders_present": [ "Antibody-mediated immunity and chemotherapy contribute; this is not pure selective kinase withdrawal, and many tumors do not respond." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 31, "pmid": "21639808", "title": "Improved survival with vemurafenib in melanoma with BRAF V600E mutation.", "citation": "Chapman PB, Hauschild A, Robert C et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. The New England journal of medicine. 2011.", "doi": "10.1056/NEJMoa1103782", "pmcid": "PMC3549296", "url": "https://pubmed.ncbi.nlm.nih.gov/21639808/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21639808/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID21639808", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "BRIM-3 enrolls 675 baseline BRAF-mutant melanoma patients; vemurafenib yields 48 percent response versus 5 percent with dacarbazine and improves early survival.", "what_it_does_not_show": "More than half lack an objective response in this report; the baseline genotype pair cannot be narrowed to responders after outcome.", "confounders_present": [ "More than half lack an objective response in this report; the baseline genotype pair cannot be narrowed to responders after outcome." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 32, "pmid": "23724913", "title": "Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.", "citation": "Shaw AT, Kim DW, Nakagawa K et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. The New England journal of medicine. 2013.", "doi": "10.1056/NEJMoa1214886", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/23724913/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23724913/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "ErratumIn: PMID26466010" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID23724913", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "PROFILE 1007 enrolls 347 ALK-positive previously treated patients and improves response and progression-free survival with crizotinib versus chemotherapy.", "what_it_does_not_show": "Interim overall survival is not significantly different; a linked erratum was not audited, and the outcome is not cure.", "confounders_present": [ "Interim overall survival is not significantly different; a linked erratum was not audited, and the outcome is not cure." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 33, "pmid": "25470694", "title": "First-line crizotinib versus chemotherapy in ALK-positive lung cancer.", "citation": "Solomon BJ, Mok T, Kim DW et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. The New England journal of medicine. 2014.", "doi": "10.1056/NEJMoa1408440", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/25470694/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25470694/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "ErratumIn: PMID26466011" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID25470694", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "PROFILE 1014 enrolls 343 untreated ALK-positive patients and improves response and progression-free survival with crizotinib versus chemotherapy.", "what_it_does_not_show": "Crossover and immature survival limit causal survival claims; linked correction details remain unexamined.", "confounders_present": [ "Crossover and immature survival limit causal survival claims; linked correction details remain unexamined." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 34, "pmid": "28586279", "title": "Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer.", "citation": "Peters S, Camidge DR, Shaw AT et al. Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. The New England journal of medicine. 2017.", "doi": "10.1056/NEJMoa1704795", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/28586279/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28586279/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID28586279", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "ALEX enrolls 303 ALK-positive patients and shows better progression and CNS control with alectinib than crizotinib.", "what_it_does_not_show": "Two active ALK agents are compared; this is not a driver-off versus driver-on test or a treatment-free endpoint.", "confounders_present": [ "Two active ALK agents are compared; this is not a driver-off versus driver-on test or a treatment-free endpoint." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 35, "pmid": "33207094", "title": "First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer.", "citation": "Shaw AT, Bauer TM, de Marinis F et al. First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer. The New England journal of medicine. 2020.", "doi": "10.1056/NEJMoa2027187", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/33207094/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33207094/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "CROWN", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "CROWN enrolls 296 ALK-positive patients and improves response and progression control with lorlatinib versus crizotinib.", "what_it_does_not_show": "Both arms inhibit ALK; toxicity and ongoing treatment remain, and later reports reuse this cohort.", "confounders_present": [ "Both arms inhibit ALK; toxicity and ongoing treatment remain, and later reports reuse this cohort." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "CROWN 296-patient trial." ] }, { "n": 36, "pmid": "38819031", "title": "Lorlatinib Versus Crizotinib in Patients With Advanced ALK-Positive Non-Small Cell Lung Cancer: 5-Year Outcomes From the Phase III CROWN Study.", "citation": "Solomon BJ, Liu G, Felip E et al. Lorlatinib Versus Crizotinib in Patients With Advanced ALK-Positive Non-Small Cell Lung Cancer: 5-Year Outcomes From the Phase III CROWN Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2024.", "doi": "10.1200/JCO.24.00581", "pmcid": "PMC11458101", "url": "https://pubmed.ncbi.nlm.nih.gov/38819031/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38819031/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "CROWN", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Five-year CROWN follow-up reports 60 percent versus 8 percent progression-free survival.", "what_it_does_not_show": "Post hoc long follow-up of the same 296 patients is not a new trial or treatment-free eradication.", "confounders_present": [ "Post hoc long follow-up of the same 296 patients is not a new trial or treatment-free eradication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "CROWN 296-patient trial follow-up." ] }, { "n": 37, "pmid": "42217582", "title": "Lorlatinib versus crizotinib as first-line treatment for advanced ALK-positive non-small-cell lung cancer: 7-year update from the phase III CROWN study.", "citation": "Shaw AT, Solomon BJ, Felip E et al. Lorlatinib versus crizotinib as first-line treatment for advanced ALK-positive non-small-cell lung cancer: 7-year update from the phase III CROWN study. Annals of oncology : official journal of the European Society for Medical Oncology. 2026.", "doi": "10.1016/j.annonc.2026.05.692", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/42217582/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42217582/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "CROWN", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Seven-year CROWN follow-up reports 55 percent versus 3 percent progression-free survival; overall survival remains immature.", "what_it_does_not_show": "Durable control occurs on treatment and does not prove cure; neither is relapse inevitable by seven years for every patient. The same CROWN cohort is reused.", "confounders_present": [ "Durable control occurs on treatment and does not prove cure; neither is relapse inevitable by seven years for every patient. The same CROWN cohort is reused." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "CROWN 296-patient trial follow-up." ] }, { "n": 38, "pmid": "11423618", "title": "Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification.", "citation": "Gorre ME, Mohammed M, Ellwood K et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science (New York, N.Y.). 2001.", "doi": "10.1126/science.1062538", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/11423618/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/11423618/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID11423618", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human specimens and mechanistic reconstruction", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Resistant CML samples contain ABL gatekeeper mutations or amplification; reconstructed mutant kinase resists imatinib.", "what_it_does_not_show": "Drug resistance with restored signaling supports continuing target dependence, not independence after successful blockade; nine selected resistant cases do not define population frequency.", "confounders_present": [ "Drug resistance with restored signaling supports continuing target dependence, not independence after successful blockade; nine selected resistant cases do not define population frequency." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 39, "pmid": "15737014", "title": "Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain.", "citation": "Pao W, Miller VA, Politi KA et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS medicine. 2005.", "doi": "10.1371/journal.pmed.0020073", "pmcid": "PMC549606", "url": "https://pubmed.ncbi.nlm.nih.gov/15737014/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15737014/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID15737014", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph15, 2:Results:paragraph16, 2:Results:paragraph17, 2:Results:paragraph18, 2:Results:paragraph19, 2:Results:paragraph26, 2:Results:paragraph29, 2:Results:paragraph31, 2:Results:paragraph32, 2:Results:paragraph34. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human specimens and mechanistic reconstruction", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "T790M appears in three of six progressing EGFR-inhibitor cases; independent RFLP and matched mutant constructs support reduced drug-sensitive phosphorylation.", "what_it_does_not_show": "One pretreatment sample is scant; sequencing sensitivity cannot exclude rare pre-existing cells. Cell-line viability contrasts have other background differences.", "confounders_present": [ "One pretreatment sample is scant; sequencing sensitivity cannot exclude rare pre-existing cells. Cell-line viability contrasts have other background differences." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "EGFR mutant model and reconstruction programme." ] }, { "n": 40, "pmid": "17463250", "title": "MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling.", "citation": "Engelman JA, Zejnullahu K, Mitsudomi T et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science (New York, N.Y.). 2007.", "doi": "10.1126/science.1141478", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/17463250/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17463250/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID17463250", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human specimens and cell perturbation", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "MET amplification activates ERBB3-mediated bypass; combined MET and EGFR inhibition restores response in resistant cells, with amplification in four of eighteen resistant patients.", "what_it_does_not_show": "Culture rescue and selected progressing biopsies do not establish universal clinical bypass frequency or durable cure.", "confounders_present": [ "Culture rescue and selected progressing biopsies do not establish universal clinical bypass frequency or durable cure." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 41, "pmid": "19759520", "title": "Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer.", "citation": "Regales L, Gong Y, Shen R et al. Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer. The Journal of clinical investigation. 2009.", "doi": "10.1172/JCI38746", "pmcid": "PMC2752070", "url": "https://pubmed.ncbi.nlm.nih.gov/19759520/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19759520/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID19759520", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "engineered autochthonous", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Combined irreversible EGFR inhibition and cetuximab regresses resistant EGFR-mutant mouse tumors and lowers receptor signaling and abundance more effectively than either alone.", "what_it_does_not_show": "Combination activity includes antibody and abundance effects; the model does not establish efficacy in every human resistance state.", "confounders_present": [ "Combination activity includes antibody and abundance effects; the model does not establish efficacy in every human resistance state." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "EGFR mutant model and reconstruction programme." ] }, { "n": 42, "pmid": "21430269", "title": "Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors.", "citation": "Sequist LV, Waltman BA, Dias-Santagata D et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Science translational medicine. 2011.", "doi": "10.1126/scitranslmed.3002003", "pmcid": "PMC3132801", "url": "https://pubmed.ncbi.nlm.nih.gov/21430269/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21430269/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID21430269", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human repeat biopsies", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Repeat biopsies from 37 progressing EGFR-mutant cancers retain EGFR mutations while showing heterogeneous mechanisms, including five small-cell transformations.", "what_it_does_not_show": "This selected progression cohort is not all treated patients; retained mutation does not itself prove the new lineage remains EGFR-dependent.", "confounders_present": [ "This selected progression cohort is not all treated patients; retained mutation does not itself prove the new lineage remains EGFR-dependent." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 43, "pmid": "22281684", "title": "Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR.", "citation": "Prahallad A, Sun C, Huang S et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012.", "doi": "10.1038/nature10868", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/22281684/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22281684/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID22281684", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell and in vivo perturbation", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "BRAF-mutant colon models resist BRAF inhibition through EGFR feedback; combined inhibition restores response, and ectopic EGFR can confer resistance in melanoma cells.", "what_it_does_not_show": "The same driver behaves differently by tissue; experimental combination rescue does not prove all baseline BRAF tumors share one maintenance rule.", "confounders_present": [ "The same driver behaves differently by tissue; experimental combination rescue does not prove all baseline BRAF tumors share one maintenance rule." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 44, "pmid": "27432227", "title": "Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer.", "citation": "Gainor JF, Dardaei L, Yoda S et al. Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer. Cancer discovery. 2016.", "doi": "10.1158/2159-8290.CD-16-0596", "pmcid": "PMC5050111", "url": "https://pubmed.ncbi.nlm.nih.gov/27432227/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27432227/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID27432227", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human biopsies and cell perturbation", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "ALK resistance biopsies and functional tests identify inhibitor-dependent spectra of secondary mutations and bypass sensitivity.", "what_it_does_not_show": "Progressor selection and the shared clinical programme limit population estimates and independence; response after resistance is context specific.", "confounders_present": [ "Progressor selection and the shared clinical programme limit population estimates and independence; response after resistance is context specific." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "MGH serial resistance-biopsy programme; exact specimen overlap is not fully resolved." ] }, { "n": 45, "pmid": "29650534", "title": "Sequential ALK Inhibitors Can Select for Lorlatinib-Resistant Compound ALK Mutations in ALK-Positive Lung Cancer.", "citation": "Yoda S, Lin JJ, Lawrence MS et al. Sequential ALK Inhibitors Can Select for Lorlatinib-Resistant Compound ALK Mutations in ALK-Positive Lung Cancer. Cancer discovery. 2018.", "doi": "10.1158/2159-8290.CD-17-1256", "pmcid": "PMC5984716", "url": "https://pubmed.ncbi.nlm.nih.gov/29650534/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29650534/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID29650534", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell selection and human specimens", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Experimental ALK selection and serial patient specimens show sequential compound mutations during inhibitor exposure.", "what_it_does_not_show": "Ba/F3 selection and selected progressing samples cannot establish that all resistance follows this genetic route.", "confounders_present": [ "Ba/F3 selection and selected progressing samples cannot establish that all resistance follows this genetic route." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "MGH serial resistance-biopsy programme; exact specimen overlap is not fully resolved." ] }, { "n": 46, "pmid": "30892989", "title": "ALK Resistance Mutations and Efficacy of Lorlatinib in Advanced Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer.", "citation": "Shaw AT, Solomon BJ, Besse B et al. ALK Resistance Mutations and Efficacy of Lorlatinib in Advanced Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2019.", "doi": "10.1200/JCO.18.02236", "pmcid": "PMC6544460", "url": "https://pubmed.ncbi.nlm.nih.gov/30892989/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30892989/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID30892989", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Exploratory lorlatinib analysis links baseline secondary ALK mutations after prior inhibitors to higher response rates in tissue and plasma subgroups.", "what_it_does_not_show": "This is a biomarker association within a treated phase-2 programme, not a randomized genotype intervention or an independent trial for each assay.", "confounders_present": [ "This is a biomarker association within a treated phase-2 programme, not a randomized genotype intervention or an independent trial for each assay." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Lorlatinib phase-2 biomarker programme, including serial resistance research." ] }, { "n": 47, "pmid": "16169465", "title": "The transcriptional repressor Snail promotes mammary tumor recurrence.", "citation": "Moody SE, Perez D, Pan TC et al. The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer cell. 2005.", "doi": "10.1016/j.ccr.2005.07.009", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/16169465/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16169465/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID16169465", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "engineered autochthonous", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Snail expression promotes recurrent mammary tumor behavior after Neu withdrawal and relates to a mesenchymal recurrence phenotype.", "what_it_does_not_show": "Forced Snail gain does not establish native necessity of Snail in every residual tumor.", "confounders_present": [ "Forced Snail gain does not establish native necessity of Snail in every residual tumor." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Inducible Neu mammary recurrence model family." ] }, { "n": 48, "pmid": "20173739", "title": "Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal.", "citation": "Sotillo R, Schvartzman JM, Socci ND et al. Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal. Nature. 2010.", "doi": "10.1038/nature08803", "pmcid": "PMC2841716", "url": "https://pubmed.ncbi.nlm.nih.gov/20173739/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20173739/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID20173739", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "engineered autochthonous", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Kras withdrawal initially regresses Kras/Mad2 lung tumors, followed by frequent recurrence with mostly absent oncogenic Kras transgene re-expression.", "what_it_does_not_show": "The present case examines the abstract; original-body credit belongs to the preceding genome-instability review. Recurrence and aneuploidy do not directly prove a persister lineage or zero remaining instability.", "confounders_present": [ "The present case examines the abstract; original-body credit belongs to the preceding genome-instability review. Recurrence and aneuploidy do not directly prove a persister lineage or zero remaining instability." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Same primary report also examined in preceding genome-instability case; contributes one unique paper to batch." ] }, { "n": 49, "pmid": "24954535", "title": "Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer.", "citation": "Kapoor A, Yao W, Ying H et al. Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer. Cell. 2014.", "doi": "10.1016/j.cell.2014.06.003", "pmcid": "PMC4109295", "url": "https://pubmed.ncbi.nlm.nih.gov/24954535/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24954535/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID31730860" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID24954535", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph0, 1:RESULTS:paragraph1, 1:RESULTS:paragraph2, 1:RESULTS:paragraph3, 1:RESULTS:paragraph4, 1:RESULTS:paragraph5, 1:RESULTS:paragraph6, 1:RESULTS:paragraph8, 1:RESULTS:paragraph9, 1:RESULTS:paragraph16. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "engineered autochthonous and functional rescue", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "After Kras withdrawal, pancreatic tumors regress and twenty of twenty-eight recur; a subset lacks transgene signaling. YAP gain substitutes for Kras, while YAP/TEAD loss or binding-defective controls suppress bypass growth.", "what_it_does_not_show": "About half reactivate the transgene through rtTA amplification; basal wild-type RAS remains. Relapse YAP-amplification and the engineered line constrain universal bypass claims; linked erratum details are unaudited.", "confounders_present": [ "About half reactivate the transgene through rtTA amplification; basal wild-type RAS remains. Relapse YAP-amplification and the engineered line constrain universal bypass claims; linked erratum details are unaudited." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Conditional pancreatic Kras model programme." ] }, { "n": 50, "pmid": "19477428", "title": "A gene expression signature associated with \"K-Ras addiction\" reveals regulators of EMT and tumor cell survival.", "citation": "Singh A, Greninger P, Rhodes D et al. A gene expression signature associated with \"K-Ras addiction\" reveals regulators of EMT and tumor cell survival. Cancer cell. 2009.", "doi": "10.1016/j.ccr.2009.03.022", "pmcid": "PMC2743093", "url": "https://pubmed.ncbi.nlm.nih.gov/19477428/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19477428/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID33689705" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID19477428", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human cell perturbation", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "KRAS-mutant cancer cell lines differ in KRAS dependency and epithelial state after RNA interference.", "what_it_does_not_show": "Cell survival screens do not establish representative native tumor maintenance; a linked correction was not audited.", "confounders_present": [ "Cell survival screens do not establish representative native tumor maintenance; a linked correction was not audited." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 51, "pmid": "20371346", "title": "A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations.", "citation": "Sharma SV, Lee DY, Li B et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell. 2010.", "doi": "10.1016/j.cell.2010.02.027", "pmcid": "PMC2851638", "url": "https://pubmed.ncbi.nlm.nih.gov/20371346/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20371346/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID20371346", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell perturbation and limited xenograft context", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Rare PC9 persisters survive concentrations far above drug IC50 with EGFR suppression; single-cell clones regenerate tolerance, withdrawal restores sensitivity, and KDM5A/HDAC/IGF1R controls separate reversible states from later T790M colonies.", "what_it_does_not_show": "Cell-line state switching does not establish every patient reservoir; expanded persisters reverse more slowly, and pharmacologic prevention is not clinical treatment-free cure.", "confounders_present": [ "Cell-line state switching does not establish every patient reservoir; expanded persisters reverse more slowly, and pharmacologic prevention is not clinical treatment-free cure." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "PC9/EGFR persister platforms reused in later studies." ] }, { "n": 52, "pmid": "21157039", "title": "Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity.", "citation": "Corbin AS, Agarwal A, Loriaux M et al. Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. The Journal of clinical investigation. 2011.", "doi": "10.1172/JCI35721", "pmcid": "PMC3007128", "url": "https://pubmed.ncbi.nlm.nih.gov/21157039/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21157039/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID21157039", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph13, 0:Publisher HTML paragraphs:paragraph15, 0:Publisher HTML paragraphs:paragraph16, 0:Publisher HTML paragraphs:paragraph21, 0:Publisher HTML paragraphs:paragraph23, 0:Publisher HTML paragraphs:paragraph24, 0:Publisher HTML paragraphs:paragraph25, 0:Publisher HTML paragraphs:paragraph30, 0:Publisher HTML paragraphs:paragraph31, 0:Publisher HTML paragraphs:paragraph47, 0:Publisher HTML paragraphs:paragraph58. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human ex vivo", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "CML stem/progenitor cultures survive strong BCR-ABL inhibition with cytokine support; phospho-CRKL/STAT5 controls, persistent inhibition and mostly Philadelphia-positive survivors address failed engagement or normal-cell carryover.", "what_it_does_not_show": "Residual phospho-signal is not literally zero activity; culture cytokines and short exposure do not prove all in vivo stem cells are wholly driver independent or dispensability of the entire BCR-ABL protein.", "confounders_present": [ "Residual phospho-signal is not literally zero activity; culture cytokines and short exposure do not prove all in vivo stem cells are wholly driver independent or dispensability of the entire BCR-ABL protein." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 53, "pmid": "11756187", "title": "Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro.", "citation": "Graham SM, Jørgensen HG, Allan E et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood. 2002.", "doi": "10.1182/blood.v99.1.319", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/11756187/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/11756187/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID11756187", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human ex vivo", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Quiescent Philadelphia-positive CML progenitors survive short imatinib culture exposure.", "what_it_does_not_show": "Without matched complete target-engagement and niche controls, survival alone cannot distinguish insufficient inhibition from signaling-independent persistence.", "confounders_present": [ "Without matched complete target-engagement and niche controls, survival alone cannot distinguish insufficient inhibition from signaling-independent persistence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 54, "pmid": "26828195", "title": "Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition.", "citation": "Hata AN, Niederst MJ, Archibald HL et al. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nature medicine. 2016.", "doi": "10.1038/nm.4040", "pmcid": "PMC4900892", "url": "https://pubmed.ncbi.nlm.nih.gov/26828195/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26828195/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID26828195", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell lineage tracing and xenograft", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Barcoding, early resistant clones, persister pools and spiked-clone kinetic controls distinguish pre-existing and later T790M routes. Late-route cells resist apoptosis despite similar EGFR/ERK inhibition; navitoclax restores death and tumor response.", "what_it_does_not_show": "Human line-response correlations do not trace original patient clones; low-frequency pretreatment mutations have detection limits, and the later route is not the only clinical route.", "confounders_present": [ "Human line-response correlations do not trace original patient clones; low-frequency pretreatment mutations have detection limits, and the later route is not the only clinical route." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "PC9/EGFR persister platforms reused in later studies." ] }, { "n": 55, "pmid": "29088702", "title": "Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition.", "citation": "Hangauer MJ, Viswanathan VS, Ryan MJ et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature. 2017.", "doi": "10.1038/nature24297", "pmcid": "PMC5933935", "url": "https://pubmed.ncbi.nlm.nih.gov/29088702/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29088702/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID29088702", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 3:Main text:paragraph0, 3:Main text:paragraph2, 3:Main text:paragraph3, 3:Main text:paragraph4, 3:Main text:paragraph6, 3:Main text:paragraph7, 3:Main text:paragraph8. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell perturbation and xenograft", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Reversible persisters selectively depend on GPX4; knockout, ferrostatin rescue and iron/lipid controls identify ferroptotic death. Unmasking GPX4 deletion after tumor shrinkage prevents relapse in the tested melanoma xenograft.", "what_it_does_not_show": "The in vivo intervention is genetic because compounds lack systemic bioavailability; continued targeted treatment, one xenograft and absent clinical safety testing do not establish treatment-free human cure.", "confounders_present": [ "The in vivo intervention is genetic because compounds lack systemic bioavailability; continued targeted treatment, one xenograft and absent clinical safety testing do not establish treatment-free human cure." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 56, "pmid": "34381210", "title": "Cycling cancer persister cells arise from lineages with distinct programs.", "citation": "Oren Y, Tsabar M, Cuoco MS et al. Cycling cancer persister cells arise from lineages with distinct programs. Nature. 2021.", "doi": "10.1038/s41586-021-03796-6", "pmcid": "PMC9209846", "url": "https://pubmed.ncbi.nlm.nih.gov/34381210/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34381210/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID34381210", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell lineage tracing and human residual specimens", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Barcoded cycling persister lineages show distinct antioxidant and fatty-acid-oxidation requirements under EGFR inhibition, with related states in human residual samples.", "what_it_does_not_show": "Culture lineage dynamics and patient transcriptional resemblance do not quantify every patient's persister fraction or prove all clinical recurrence is state driven.", "confounders_present": [ "Culture lineage dynamics and patient transcriptional resemblance do not quantify every patient's persister fraction or prove all clinical recurrence is state driven." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "EGFR persister platform and investigators; barcode approach adds controls, not independent clinical validation." ] }, { "n": 57, "pmid": "37407818", "title": "Therapy-induced APOBEC3A drives evolution of persistent cancer cells.", "citation": "Isozaki H, Sakhtemani R, Abbasi A et al. Therapy-induced APOBEC3A drives evolution of persistent cancer cells. Nature. 2023.", "doi": "10.1038/s41586-023-06303-1", "pmcid": "PMC10804446", "url": "https://pubmed.ncbi.nlm.nih.gov/37407818/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37407818/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID37407818", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell perturbation and experimental tumors", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "APOBEC3A loss reduces treatment-associated mutagenesis and delays resistance in the experimental systems.", "what_it_does_not_show": "Delay does not establish a sole universal resistance mechanism or spontaneous cancer initiation by APOBEC.", "confounders_present": [ "Delay does not establish a sole universal resistance mechanism or spontaneous cancer initiation by APOBEC." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 58, "pmid": "38702301", "title": "Focal adhesion kinase-YAP signaling axis drives drug-tolerant persister cells and residual disease in lung cancer.", "citation": "Haderk F, Chou YT, Cech L et al. Focal adhesion kinase-YAP signaling axis drives drug-tolerant persister cells and residual disease in lung cancer. Nature communications. 2024.", "doi": "10.1038/s41467-024-47423-0", "pmcid": "PMC11068778", "url": "https://pubmed.ncbi.nlm.nih.gov/38702301/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38702301/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID38702301", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "patient-derived and syngeneic perturbation", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "FAK-YAP inhibition with EGFR inhibitors reduces residual disease and improves tumor response in tested experimental systems.", "what_it_does_not_show": "Combined intervention and selected models do not establish a safe or universally curative clinical regimen.", "confounders_present": [ "Combined intervention and selected models do not establish a safe or universally curative clinical regimen." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 59, "pmid": "36535627", "title": "Single-Cell Analysis Reveals Transcriptomic Features of Drug-Tolerant Persisters and Stromal Adaptation in a Patient-Derived EGFR-Mutated Lung Adenocarcinoma Xenograft Model.", "citation": "Moghal N, Li Q, Stewart EL et al. Single-Cell Analysis Reveals Transcriptomic Features of Drug-Tolerant Persisters and Stromal Adaptation in a Patient-Derived EGFR-Mutated Lung Adenocarcinoma Xenograft Model. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2023.", "doi": "10.1016/j.jtho.2022.12.003", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/36535627/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36535627/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID37999691" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID36535627", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "single patient-derived xenograft", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Residual and baseline tumors in an EGFR-mutant lung adenocarcinoma PDX retain genomic clonal architecture; rare baseline cells have DTP-like transcripts, and CAF populations shift toward IL6 production with in vitro CAF-state conversion.", "what_it_does_not_show": "A single PDX, association and state similarity do not prove all patient reservoirs or native relapse dependency; linked correction details are unaudited.", "confounders_present": [ "A single PDX, association and state similarity do not prove all patient reservoirs or native relapse dependency; linked correction details are unaudited." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 60, "pmid": "42314664", "title": "Targeting TROP2 in drug-tolerant persister cells delays EGFR tyrosine kinase inhibitor resistance in non-small-cell lung cancer.", "citation": "Liao J, Yao W, Yu Y et al. Targeting TROP2 in drug-tolerant persister cells delays EGFR tyrosine kinase inhibitor resistance in non-small-cell lung cancer. Cancer cell. 2026.", "doi": "10.1016/j.ccell.2026.05.020", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/42314664/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42314664/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID42314664", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "preclinical perturbation and preliminary clinical cohort", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "TROP2 derepression accompanies EGFR-inhibitor persisters; experimental TROP2-directed combination delays relapse, with preliminary phase-2 observations.", "what_it_does_not_show": "Preliminary nonrandomized observations are not controlled treatment-free cure or universal residual-cell dependence.", "confounders_present": [ "Preliminary nonrandomized observations are not controlled treatment-free cure or universal residual-cell dependence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 61, "pmid": "20965785", "title": "Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial.", "citation": "Mahon FX, Réa D, Guilhot J et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. The Lancet. Oncology. 2010.", "doi": "10.1016/S1470-2045(10)70233-3", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/20965785/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20965785/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID20965785", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "contradicts", "what_it_shows": "STIM tests stopping imatinib after at least two years of deep molecular remission; many relapse, while a selected fraction maintains molecular remission off treatment and relapsers respond to rechallenge.", "what_it_does_not_show": "Enrollment selects prior deep responders, not all newly diagnosed CML; persistent molecular remission is not proof of absence of all leukemic cells. It contradicts continuous-drug necessity for every patient.", "confounders_present": [ "Enrollment selects prior deep responders, not all newly diagnosed CML; persistent molecular remission is not proof of absence of all leukemic cells. It contradicts continuous-drug necessity for every patient." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 62, "pmid": "24336571", "title": "Genome-scale CRISPR-Cas9 knockout screening in human cells.", "citation": "Shalem O, Sanjana NE, Hartenian E et al. Genome-scale CRISPR-Cas9 knockout screening in human cells. Science (New York, N.Y.). 2014.", "doi": "10.1126/science.1247005", "pmcid": "PMC4089965", "url": "https://pubmed.ncbi.nlm.nih.gov/24336571/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24336571/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID24336571", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell genome-wide perturbation", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Genome-scale CRISPR selection identifies diverse genes whose loss confers vemurafenib resistance.", "what_it_does_not_show": "One cellular resistance screen is not a representative pan-cancer tumor-maintenance map or proof of one dominant oncogene across most cancers.", "confounders_present": [ "One cellular resistance screen is not a representative pan-cancer tumor-maintenance map or proof of one dominant oncogene across most cancers." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 63, "pmid": "42171647", "title": "Genetic Drivers of Sensitivity or Resistance to RAS(ON) Multiselective Inhibitors in NRAS-Mutated Melanoma.", "citation": "Foth M, Kim W, O'Toole K et al. Genetic Drivers of Sensitivity or Resistance to RAS(ON) Multiselective Inhibitors in NRAS-Mutated Melanoma. Cancer research. 2026.", "doi": "10.1158/0008-5472.CAN-26-1313", "pmcid": "PMC13335394", "url": "https://pubmed.ncbi.nlm.nih.gov/42171647/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42171647/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID41446219" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID42171647", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "preclinical perturbation and two clinical cases", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "NRAS melanoma RAS-on response and resistance depend on alterations including cyclophilin-A and MAP2K1; two clinical cases show divergent response.", "what_it_does_not_show": "Two cases do not define response frequency or clinical cure. The peer-reviewed report replaces its earlier preprint without double counting.", "confounders_present": [ "Two cases do not define response frequency or clinical cure. The peer-reviewed report replaces its earlier preprint without double counting." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 64, "pmid": "41670434", "title": "Abrogation of Oncogenic RAS Signaling by a RAS(ON) Inhibitor Doublet Primes Immune-Refractory KRASG12C-Mutant NSCLC for Immune Checkpoint Blockade.", "citation": "Wei X, Blaj C, Ali Al-Radhawi M et al. Abrogation of Oncogenic RAS Signaling by a RAS(ON) Inhibitor Doublet Primes Immune-Refractory KRASG12C-Mutant NSCLC for Immune Checkpoint Blockade. Cancer discovery. 2026.", "doi": "10.1158/2159-8290.CD-25-1616", "pmcid": "PMC13223541", "url": "https://pubmed.ncbi.nlm.nih.gov/41670434/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41670434/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID41670434", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "preclinical immunocompetent perturbation", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "RAS-on inhibitor combinations regress tested tumors and require host T cells for deeper responses.", "what_it_does_not_show": "These are preclinical results, not demonstrated regression or complete responses in NSCLC patients; host dependence limits purely cell-autonomous interpretation.", "confounders_present": [ "These are preclinical results, not demonstrated regression or complete responses in NSCLC patients; host dependence limits purely cell-autonomous interpretation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "RAS-on inhibitor drug-class programme shared with pancreatic immune response work." ] }, { "n": 65, "pmid": "42329099", "title": "EML4-ALK mediates resistance to KRAS G12C inhibition and induces an oncogenic dependency by rewiring signaling through the wild-type RAS pathway.", "citation": "Scaparone P, Mira A, Cheong TC et al. EML4-ALK mediates resistance to KRAS G12C inhibition and induces an oncogenic dependency by rewiring signaling through the wild-type RAS pathway. Cancer discovery. 2026.", "doi": "10.1158/2159-8290.CD-25-0477", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/42329099/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42329099/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID42329099", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell selection and preclinical perturbation", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Acquired EML4-ALK restores wild-type RAS signaling under KRAS-G12C inhibition; continued KRAS blockade creates a context-specific ALK sensitivity and schedule-dependent combination response.", "what_it_does_not_show": "Selected models and treatment sequence do not establish population prevalence or clinical eradication.", "confounders_present": [ "Selected models and treatment sequence do not establish population prevalence or clinical eradication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 66, "pmid": "40057911", "title": "T-cell Dependency of Tumor Regressions and Complete Responses with RAS(ON) Multi-selective Inhibition in Preclinical Models of Pancreatic Ductal Adenocarcinoma.", "citation": "Orlen M, Vostrejs WP, Sor R et al. T-cell Dependency of Tumor Regressions and Complete Responses with RAS(ON) Multi-selective Inhibition in Preclinical Models of Pancreatic Ductal Adenocarcinoma. Cancer discovery. 2025.", "doi": "10.1158/2159-8290.CD-24-1475", "pmcid": "PMC12319402", "url": "https://pubmed.ncbi.nlm.nih.gov/40057911/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40057911/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID40057911", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "preclinical immunocompetent perturbation", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "RAS-on inhibition regresses pancreatic tumors in tested models; T cells and dendritic cells are required for the deeper response, with greater complete responses after immune combination.", "what_it_does_not_show": "Complete responses are preclinical and combination dependent; shared drug-class programmes are not independent clinical validation or treatment-free cure.", "confounders_present": [ "Complete responses are preclinical and combination dependent; shared drug-class programmes are not independent clinical validation or treatment-free cure." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "RAS-on inhibitor drug-class programme shared with subsequent immune combination work." ] } ], "verification_summary": { "load_bearing_claims_checked": 70, "verified": 70, "unverified": 0, "contradicted": 0, "note": "Verified attribution is distinct from mechanism truth or complete body access." }, "factual_issues_found": [], "cap_rules_applied": [], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Cancers with prospectively defined driver–tumor pairs depend on continuous dominant oncogene signaling for maintenance, so selective signaling withdrawal produces tumor regression.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "The index explicitly permits scope-matched specific-pair maintenance scoring. Η applies to the assembled evidence for SC1, which covers weaknesses of forced models with endogenous conditional perturbation, resistance reconstruction and molecularly enrolled human trial families. The same convergence does not upgrade SC2 or SC3. Their Γ scores follow missing full-scope thresholds, rather than applying a literal in-vitro-only cap to a mixed in vivo/clinical corpus.", "note": "Convergent lines are assessed as a set; one weak leg is not re-capped over the assembled case." } ], "boundary_check_BGD": [ { "subclaim_id": "SC1", "field_valid_perturbation_quote": "\n- Endogenous genetic manipulation in autochthonous models\n- Patient-derived system perturbation with matched rescue AND in vivo confirmation\n- Clonal tracking demonstrating persistence of dependency through selection pressure", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID16705038, PMID22606359, PMID23532334, PMID18716624, PMID23475959, PMID12637609, PMID20573926, PMID11248153, PMID21639808, PMID25470694, PMID28586279, PMID11423618, PMID15737014, PMID19759520", "gamma_hard_rules_triggered": [ "Cell-line viability and transformation capacity alone do not establish native cancer-maintenance necessity.", "Patient genotype must be known before response; retrospective responder-selected mutation discovery is separate from molecularly enrolled trials.", "A drug-resistant kinase with restored signaling is not independence after successful driver blockade.", "Radiographic response, deep molecular remission and on-treatment progression-free survival are not sterile treatment-free eradication.", "The assembled endogenous, genetic, mechanistic and clinical evidence is assessed as a set rather than re-capped by its weakest assay class." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Η is supported for the prospectively named maintenance/regression pairs by endogenous conditional KRAS and MYC interventions, orthogonal EGFR withdrawal/drug controls, resistance alleles and several molecularly enrolled randomized trial families. This means causal regression in defined settings, not every enrolled tumor responding or every tumor cell requiring the driver. Nonresponse and context-specific bypass are major exceptions, preventing Θ and Ω.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC2", "field_valid_perturbation_quote": "\n- Endogenous genetic manipulation in autochthonous models\n- Patient-derived system perturbation with matched rescue AND in vivo confirmation\n- Clonal tracking demonstrating persistence of dependency through selection pressure", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "Cell-line viability and transformation capacity alone do not establish native cancer-maintenance necessity.", "Patient genotype must be known before response; retrospective responder-selected mutation discovery is separate from molecularly enrolled trials.", "A drug-resistant kinase with restored signaling is not independence after successful driver blockade.", "Radiographic response, deep molecular remission and on-treatment progression-free survival are not sterile treatment-free eradication.", "The assembled endogenous, genetic, mechanistic and clinical evidence is assessed as a set rather than re-capped by its weakest assay class." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Experimental dual-driver and tissue comparisons, heterogeneous KRAS cell dependency and genome-wide resistance screens show context dependence. These reports do not constitute a representative native pan-cancer maintenance map establishing a single dominant dependency in most cancers. The broad model has mechanistic plausibility, but its prespecified denominator and matching causal test are missing.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC3", "field_valid_perturbation_quote": "\n- Endogenous genetic manipulation in autochthonous models\n- Patient-derived system perturbation with matched rescue AND in vivo confirmation\n- Clonal tracking demonstrating persistence of dependency through selection pressure", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "Cell-line viability and transformation capacity alone do not establish native cancer-maintenance necessity.", "Patient genotype must be known before response; retrospective responder-selected mutation discovery is separate from molecularly enrolled trials.", "A drug-resistant kinase with restored signaling is not independence after successful driver blockade.", "Radiographic response, deep molecular remission and on-treatment progression-free survival are not sterile treatment-free eradication.", "The assembled endogenous, genetic, mechanistic and clinical evidence is assessed as a set rather than re-capped by its weakest assay class." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Initial regression and prolonged progression-free survival differ from eradication. Target-engaged human stem-cell survival, reversible tolerance, late resistance, transgene-independent recurrence and responder-selected treatment cessation contradict universal residual-cell elimination. Selected osteosarcoma differentiation or four-week off-treatment tumor absence after repeated Omomyc does not establish general lifelong cure.", "ceiling_from_boundary_check": "Γ" } ], "thresholds_tested": [ { "subclaim_id": "SC1", "threshold": "Δ", "requirement_quoted": "Requires at least one meaningful causal perturbation showing the proposed mechanism contributes to initiation, maintenance, or relapse.", "satisfied": "yes", "supporting_evidence": [ "[5] Both EGFR transgene withdrawal and erlotinib during continued doxycycline regress mutant-EGFR tumors; placebo and KRAS tumors fail the drug response.", "[12] Switching off an endogenous conditional KRAS fusion allele regresses pancreatic tumors.", "[15] BIM or PUMA loss reduces apoptosis and slows HER2-withdrawal regression; PUMA loss also impairs EGFR-withdrawal lung regression. Constitutive AKT/MEK separates downstream apoptotic routes.", "[17] Omomyc inhibition of endogenous MYC regresses KRAS-driven lung tumors with reversible effects on normal regenerative tissues.", "[18] Repeated four-week Omomyc on/off cycles lower KRAS-lung tumor recurrence; after eight cycles, three of four mice have no scored tumors after four weeks off. Refractory lesions suppress Omomyc expression.", "[23] IRIS randomizes 1106 CML patients and shows better cytogenetic response and progression control with imatinib than interferon plus cytarabine.", "[27] Baseline EGFR-mutant NEJ002 enrollment yields 73.7 percent response and 10.8-month median progression-free survival with gefitinib, versus 30.7 percent and 5.4 months with chemotherapy.", "[30] HER2-selected metastatic breast cancer shows greater response and longer survival with trastuzumab plus chemotherapy than chemotherapy alone.", "[31] BRIM-3 enrolls 675 baseline BRAF-mutant melanoma patients; vemurafenib yields 48 percent response versus 5 percent with dacarbazine and improves early survival.", "[33] PROFILE 1014 enrolls 343 untreated ALK-positive patients and improves response and progression-free survival with crizotinib versus chemotherapy.", "[34] ALEX enrolls 303 ALK-positive patients and shows better progression and CNS control with alectinib than crizotinib.", "[38] Resistant CML samples contain ABL gatekeeper mutations or amplification; reconstructed mutant kinase resists imatinib.", "[39] T790M appears in three of six progressing EGFR-inhibitor cases; independent RFLP and matched mutant constructs support reduced drug-sensitive phosphorylation.", "[41] Combined irreversible EGFR inhibition and cetuximab regresses resistant EGFR-mutant mouse tumors and lowers receptor signaling and abundance more effectively than either alone." ], "what_would_cross_it": "" }, { "subclaim_id": "SC1", "threshold": "Ε", "requirement_quoted": "Requires context-specific causal validity with explicit limits. Cancer stem cells often belong here when a stem-like hierarchy exists in some tumor contexts but fails as a universal model.", "satisfied": "yes", "supporting_evidence": [ "[5] Both EGFR transgene withdrawal and erlotinib during continued doxycycline regress mutant-EGFR tumors; placebo and KRAS tumors fail the drug response.", "[12] Switching off an endogenous conditional KRAS fusion allele regresses pancreatic tumors.", "[15] BIM or PUMA loss reduces apoptosis and slows HER2-withdrawal regression; PUMA loss also impairs EGFR-withdrawal lung regression. Constitutive AKT/MEK separates downstream apoptotic routes.", "[17] Omomyc inhibition of endogenous MYC regresses KRAS-driven lung tumors with reversible effects on normal regenerative tissues.", "[18] Repeated four-week Omomyc on/off cycles lower KRAS-lung tumor recurrence; after eight cycles, three of four mice have no scored tumors after four weeks off. Refractory lesions suppress Omomyc expression.", "[23] IRIS randomizes 1106 CML patients and shows better cytogenetic response and progression control with imatinib than interferon plus cytarabine.", "[27] Baseline EGFR-mutant NEJ002 enrollment yields 73.7 percent response and 10.8-month median progression-free survival with gefitinib, versus 30.7 percent and 5.4 months with chemotherapy.", "[30] HER2-selected metastatic breast cancer shows greater response and longer survival with trastuzumab plus chemotherapy than chemotherapy alone.", "[31] BRIM-3 enrolls 675 baseline BRAF-mutant melanoma patients; vemurafenib yields 48 percent response versus 5 percent with dacarbazine and improves early survival.", "[33] PROFILE 1014 enrolls 343 untreated ALK-positive patients and improves response and progression-free survival with crizotinib versus chemotherapy.", "[34] ALEX enrolls 303 ALK-positive patients and shows better progression and CNS control with alectinib than crizotinib.", "[38] Resistant CML samples contain ABL gatekeeper mutations or amplification; reconstructed mutant kinase resists imatinib.", "[39] T790M appears in three of six progressing EGFR-inhibitor cases; independent RFLP and matched mutant constructs support reduced drug-sensitive phosphorylation.", "[41] Combined irreversible EGFR inhibition and cetuximab regresses resistant EGFR-mutant mouse tumors and lowers receptor signaling and abundance more effectively than either alone." ], "what_would_cross_it": "" }, { "subclaim_id": "SC1", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Independent causal confirmation across models\n- Reduced viability of major alternatives\n- Relevance beyond one assay class", "satisfied": "yes", "supporting_evidence": [ "[5] Both EGFR transgene withdrawal and erlotinib during continued doxycycline regress mutant-EGFR tumors; placebo and KRAS tumors fail the drug response.", "[12] Switching off an endogenous conditional KRAS fusion allele regresses pancreatic tumors.", "[15] BIM or PUMA loss reduces apoptosis and slows HER2-withdrawal regression; PUMA loss also impairs EGFR-withdrawal lung regression. Constitutive AKT/MEK separates downstream apoptotic routes.", "[17] Omomyc inhibition of endogenous MYC regresses KRAS-driven lung tumors with reversible effects on normal regenerative tissues.", "[18] Repeated four-week Omomyc on/off cycles lower KRAS-lung tumor recurrence; after eight cycles, three of four mice have no scored tumors after four weeks off. Refractory lesions suppress Omomyc expression.", "[23] IRIS randomizes 1106 CML patients and shows better cytogenetic response and progression control with imatinib than interferon plus cytarabine.", "[27] Baseline EGFR-mutant NEJ002 enrollment yields 73.7 percent response and 10.8-month median progression-free survival with gefitinib, versus 30.7 percent and 5.4 months with chemotherapy.", "[30] HER2-selected metastatic breast cancer shows greater response and longer survival with trastuzumab plus chemotherapy than chemotherapy alone.", "[31] BRIM-3 enrolls 675 baseline BRAF-mutant melanoma patients; vemurafenib yields 48 percent response versus 5 percent with dacarbazine and improves early survival.", "[33] PROFILE 1014 enrolls 343 untreated ALK-positive patients and improves response and progression-free survival with crizotinib versus chemotherapy.", "[34] ALEX enrolls 303 ALK-positive patients and shows better progression and CNS control with alectinib than crizotinib.", "[38] Resistant CML samples contain ABL gatekeeper mutations or amplification; reconstructed mutant kinase resists imatinib.", "[39] T790M appears in three of six progressing EGFR-inhibitor cases; independent RFLP and matched mutant constructs support reduced drug-sensitive phosphorylation.", "[41] Combined irreversible EGFR inhibition and cetuximab regresses resistant EGFR-mutant mouse tumors and lowers receptor signaling and abundance more effectively than either alone." ], "what_would_cross_it": "" }, { "subclaim_id": "SC1", "threshold": "Η", "requirement_quoted": "Requires:\n- Strong endogenous evidence\n- Therapeutic or mechanistic consequence\n- Reproducibility across disease settings within the claimed scope", "satisfied": "yes", "supporting_evidence": [ "[5] Both EGFR transgene withdrawal and erlotinib during continued doxycycline regress mutant-EGFR tumors; placebo and KRAS tumors fail the drug response.", "[12] Switching off an endogenous conditional KRAS fusion allele regresses pancreatic tumors.", "[15] BIM or PUMA loss reduces apoptosis and slows HER2-withdrawal regression; PUMA loss also impairs EGFR-withdrawal lung regression. Constitutive AKT/MEK separates downstream apoptotic routes.", "[17] Omomyc inhibition of endogenous MYC regresses KRAS-driven lung tumors with reversible effects on normal regenerative tissues.", "[18] Repeated four-week Omomyc on/off cycles lower KRAS-lung tumor recurrence; after eight cycles, three of four mice have no scored tumors after four weeks off. Refractory lesions suppress Omomyc expression.", "[23] IRIS randomizes 1106 CML patients and shows better cytogenetic response and progression control with imatinib than interferon plus cytarabine.", "[27] Baseline EGFR-mutant NEJ002 enrollment yields 73.7 percent response and 10.8-month median progression-free survival with gefitinib, versus 30.7 percent and 5.4 months with chemotherapy.", "[30] HER2-selected metastatic breast cancer shows greater response and longer survival with trastuzumab plus chemotherapy than chemotherapy alone.", "[31] BRIM-3 enrolls 675 baseline BRAF-mutant melanoma patients; vemurafenib yields 48 percent response versus 5 percent with dacarbazine and improves early survival.", "[33] PROFILE 1014 enrolls 343 untreated ALK-positive patients and improves response and progression-free survival with crizotinib versus chemotherapy.", "[34] ALEX enrolls 303 ALK-positive patients and shows better progression and CNS control with alectinib than crizotinib.", "[38] Resistant CML samples contain ABL gatekeeper mutations or amplification; reconstructed mutant kinase resists imatinib.", "[39] T790M appears in three of six progressing EGFR-inhibitor cases; independent RFLP and matched mutant constructs support reduced drug-sensitive phosphorylation.", "[41] Combined irreversible EGFR inhibition and cetuximab regresses resistant EGFR-mutant mouse tumors and lowers receptor signaling and abundance more effectively than either alone." ], "what_would_cross_it": "" }, { "subclaim_id": "SC1", "threshold": "Θ", "requirement_quoted": "Requires that the mechanism explains most of the claimed cancer behavior with only minor exceptions.", "satisfied": "no", "supporting_evidence": [ "[5] Both EGFR transgene withdrawal and erlotinib during continued doxycycline regress mutant-EGFR tumors; placebo and KRAS tumors fail the drug response.", "[12] Switching off an endogenous conditional KRAS fusion allele regresses pancreatic tumors.", "[15] BIM or PUMA loss reduces apoptosis and slows HER2-withdrawal regression; PUMA loss also impairs EGFR-withdrawal lung regression. Constitutive AKT/MEK separates downstream apoptotic routes.", "[17] Omomyc inhibition of endogenous MYC regresses KRAS-driven lung tumors with reversible effects on normal regenerative tissues.", "[18] Repeated four-week Omomyc on/off cycles lower KRAS-lung tumor recurrence; after eight cycles, three of four mice have no scored tumors after four weeks off. Refractory lesions suppress Omomyc expression.", "[23] IRIS randomizes 1106 CML patients and shows better cytogenetic response and progression control with imatinib than interferon plus cytarabine.", "[27] Baseline EGFR-mutant NEJ002 enrollment yields 73.7 percent response and 10.8-month median progression-free survival with gefitinib, versus 30.7 percent and 5.4 months with chemotherapy.", "[30] HER2-selected metastatic breast cancer shows greater response and longer survival with trastuzumab plus chemotherapy than chemotherapy alone.", "[31] BRIM-3 enrolls 675 baseline BRAF-mutant melanoma patients; vemurafenib yields 48 percent response versus 5 percent with dacarbazine and improves early survival.", "[33] PROFILE 1014 enrolls 343 untreated ALK-positive patients and improves response and progression-free survival with crizotinib versus chemotherapy.", "[34] ALEX enrolls 303 ALK-positive patients and shows better progression and CNS control with alectinib than crizotinib.", "[38] Resistant CML samples contain ABL gatekeeper mutations or amplification; reconstructed mutant kinase resists imatinib.", "[39] T790M appears in three of six progressing EGFR-inhibitor cases; independent RFLP and matched mutant constructs support reduced drug-sensitive phosphorylation.", "[41] Combined irreversible EGFR inhibition and cetuximab regresses resistant EGFR-mutant mouse tumors and lowers receptor signaling and abundance more effectively than either alone." ], "what_would_cross_it": "To cross Θ, explain most behavior within every named baseline pair with only minor exceptions, including prospective nonresponders and residual compartments; independently verify target engagement, baseline modifiers, driver restoration and long-term course without responder-defined scope. Ω additionally needs necessity and sufficiency across those cancer contexts." }, { "subclaim_id": "SC2", "threshold": "Δ", "requirement_quoted": "Requires at least one meaningful causal perturbation showing the proposed mechanism contributes to initiation, maintenance, or relapse.", "satisfied": "no", "supporting_evidence": [], "what_would_cross_it": "Test a prespecified representative pan-cancer sample with native allele-specific withdrawal and matched restoration, direct target engagement and in vivo maintenance endpoints. Establish the one-driver frequency before assigning a general causal rule." }, { "subclaim_id": "SC3", "threshold": "Δ", "requirement_quoted": "Requires at least one meaningful causal perturbation showing the proposed mechanism contributes to initiation, maintenance, or relapse.", "satisfied": "no", "supporting_evidence": [], "what_would_cross_it": "After verified driver withdrawal, lineage-track all detectable residual compartments and compare treatment-free recurrence with matched restoration or selective reservoir elimination in independent native models; test prospective cessation cohorts without treating assay negativity as absolute absence." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "Continued doxycycline during erlotinib, placebo, low drug dose and KRAS tumors distinguish EGFR inhibition from reduced transgene induction or nonspecific regression (PMID16705038).", "Matched T790M constructs, total EGFR/actin controls and independent mutation detection separate resistance of the target from absence of drug exposure (PMID15737014).", "BIM/PUMA loss and constitutive AKT/MEK show that target withdrawal requires a competent apoptotic route (PMID23532334).", "Cytokine titration, normal cells, mostly Philadelphia-positive survivors and phospho-CRKL/STAT5 immunoblotting address residual CML survival despite inhibition (PMID21157039).", "Single-cell clones, drug washout and eight negative compounds distinguish reversible tolerance from a stable rare mutation or nonspecific toxicity (PMID20371346).", "RFP-spiked clones, barcodes and timing contrast rare pre-existing T790M with late persister-derived routes (PMID26828195).", "YAP-binding-defective mutants, two shRNAs, GFP and Kras-expressing controls distinguish YAP/TEAD bypass from nonspecific growth inhibition (PMID24954535).", "GPX4 wild type, knockout, ferrostatin rescue and parental tumor growth distinguish state-specific residual dependence from general inability to form tumors (PMID29088702)." ], "note": "Scope is fixed by baseline driver, tissue, treatment history and endpoint. EGFR mutation discovery selected after response is not prospective enrollment; IPASS has clinically selected enrollment with a molecular subsample; NEJ002 and other molecular trials supply baseline denominators. BRAF colon versus melanoma, dual-driver models, CML stem compartments and host-immune dependence are real boundaries. STIM is deliberately selected by prior deep response and cannot estimate all-patient drug-free success." }, "falsification_patterns_met": [ { "pattern": "Residual phenotype persists despite target inhibition", "evidence": "Strongly inhibited CML stem/progenitor cultures survive with cytokines, and genotype-defined cohorts retain nonresponders and later persistent disease. These falsify all-cell elimination, while not disproving bulk regression (PMID21157039,21639808,26828195).", "downgrade_applied": false }, { "pattern": "Dependency can change through selection", "evidence": "YAP/TEAD bypass after verified Kras withdrawal and lineage conversion with retained EGFR mutations contest an immutable dominant node (PMID24954535,21430269).", "downgrade_applied": false } ], "pitfalls_flagged": [ { "pitfall": "Scope defined by outcome", "where": "Responder-selected discovery and STIM deep-response enrollment have separate limitations; SC1 stays within baseline-defined cohorts including nonresponders." }, { "pitfall": "Regression substituted for eradication", "where": "MRI absence, deep molecular response, prolonged on-treatment PFS and four-week off-treatment histology remain distinct." }, { "pitfall": "Target resistance confused with target independence", "where": "Gatekeeper mutations, rtTA reactivation and genuine YAP bypass are separately appraised." }, { "pitfall": "Cell-state plasticity ignored", "where": "Single-cell reversibility, slow reversion after expansion and two T790M routes remain explicit." }, { "pitfall": "Repeated reports counted as replication", "where": "FLAURA/CROWN outcomes and related mouse programmes are grouped." }, { "pitfall": "Provider summary substituted for original evidence", "where": "Only one of eight requested Consensus body checks was directly comparable; seven provider gaps earn no body credit." } ], "causal_tally_audit": { "tally_claimed_by_document": 51, "tally_after_audit": 51, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "Positive contrasts are not independent causal lines. Follow-up efficacy reports are not retallied as new perturbations.", "STIM cessation, target-engaged survival and observational biopsy contrasts do not inflate positive-support tallies.", "Transformation discovery and genomic resistance screens are not whole-tumor native maintenance interventions." ] }, "steelman": { "case_one_rung_higher": "One rung higher Θ: long-term ALK control and convergent genetic/clinical regression could imply that the mechanism explains most behavior in the named pairs. But substantial initial nonresponse, primary tissue-specific feedback, apoptosis/host requirements and residual-cell escape are major rather than minor exceptions.", "case_one_rung_lower": "One rung lower Ζ: many genetic studies force transgene expression and selective drugs are pleiotropic, so independent causal confirmation might be all that is justified. That argument overlooks endogenous conditional KRAS, inhibition of native MYC, orthogonal drug/withdrawal controls and independently molecularly enrolled clinical consequence across several tumor settings.", "which_rejected": "Ζ understates the assembled endogenous and therapeutic evidence within SC1; Θ overstates completeness within the baseline cohorts. Retain Η with Moderate confidence and keep the broader SC2/SC3 grades separate.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: In baseline molecularly defined driver–tumor cohorts and matched native models, combine allele-specific withdrawal with direct engagement measures, matched driver restoration and longitudinal lineage-resolved residual-cell tracking. Prospectively include nonresponders; perturb candidate bypass and reservoir dependencies separately. Follow sustained control both during treatment and after predefined cessation." }, "final_score": { "hsef_level": "Η", "hsef_descriptor": "Strong convergent causal evidence, intervention-sensitive", "confidence": "Moderate", "confidence_rationale": "Multiple independent studies across several disease settings with partial replication, but methodological heterogeneity persists: many founding perturbations share model programmes, several clinical lines compare active inhibitors rather than driver-on versus driver-off, and control sets differ across assay classes. Evidence density and reproducibility set the Moderate band, not the reviewer's access depth and not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "The preregistered scope-matched rule reports SC1 at Η: endogenous conditional-driver and common-conduit interventions, genetic withdrawal, mechanistic resistance/rescue and baseline molecularly defined clinical trials converge on tumor-maintenance dependence across named pairs. Significant primary nonresponse, host/apoptosis dependence and persistence prevent Θ or Ω. SC2 pan-cancer one-driver generalization and SC3 residual-cell eradication remain Γ as broader mechanistic claims without matching general causal validation." }, "role_of_mechanism": { "classification": "primary driver", "derivation_step_matched": 3, "derivation": "Apply the direction procedure to the scoped dominant-driver mechanism: it is not demonstrated to be produced by tumor regression, and causal dependence is present. Genetic engagement initiates tumors in defined experimental lineages, selective withdrawal substantially regresses or delays established disease, and switch/restoration or target-resistance contrasts identify a rate-limiting maintenance node. Thus primary driver is supported for the named bulk-tumor settings. This role does not assert that all baseline tumors or every residual compartment require the same node; initiating sufficiency from forced expression alone is not generalized to every sporadic cancer.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "The named 2026 RAS-on genotype/resistance and immune-combination programmes are active causal mechanistic work in preclinical models (PMID42171647,41670434,40057911), but none addresses the boundary check that would cross the next threshold: no named ongoing experiment prospectively maps nonresponse within each baseline pair or tests residual-compartment elimination with matched restoration. The review asserts no recruiting trial and no imminent outcome, which is the framework's definition of mechanistic rather than decisive work.", "justification": "The named 2026 RAS-on genotype/resistance and immune-combination programmes are active causal mechanistic work in preclinical models (PMID42171647,41670434,40057911), but none addresses the boundary check that would cross the next threshold: no named ongoing experiment prospectively maps nonresponse within each baseline pair or tests residual-compartment elimination with matched restoration. The review asserts no recruiting trial and no imminent outcome, which is the framework's definition of mechanistic rather than decisive work." }, "stability": { "value": "Stable", "trigger": "No named pending result is shown to be likely to move the scoped Η grade imminently; new residual-disease results could change the separate eradication subclaim.", "justification": "No named pending result is shown to be likely to move the scoped Η grade imminently; new residual-disease results could change the separate eradication subclaim." }, "divergence": { "implied_level": null, "implied_level_basis": "No single field-implied level is defensible from conflicting framings.", "assessed_level": "Η", "gap_in_rungs": null, "value": "Contested", "justification": "No manufactured field consensus or arithmetic gap. Artifact for the split: the field's own framing of oncogene addiction as a near-universal single-node vulnerability implies a high rung, while the same literature's documented primary nonresponse, tissue-specific feedback and target-engaged residual survival imply a much lower one for the broad claim (PMID20573926,21639808,22281684,21157039)." }, "calibration_note": "M/S/D never modify HSEF level or confidence." }, "change_record": { "applies": false, "prior_level": "Ranking categorical verdict visible; no prior letter used as a target", "prior_confidence": null, "prior_source": null, "derived_before_consulting_prior": false, "new_level": "Η", "direction": "newly assigned", "what_moved_it": "Fresh primary evidence appraisal; not blinded.", "divergence_from_other_reviewers": null }, "proposed_decisive_experiments": [ { "name": "Registered boundary experiment", "experiment": "In baseline molecularly defined driver–tumor cohorts and matched native models, combine allele-specific withdrawal with direct engagement measures, matched driver restoration and longitudinal lineage-resolved residual-cell tracking. Prospectively include nonresponders; perturb candidate bypass and reservoir dependencies separately. Follow sustained control both during treatment and after predefined cessation.", "readout": "Bulk regression, apoptosis, driver signaling, residual clone fate, lineage transition, relapse and treatment-free survival over a prespecified interval", "critical_control": "Restoration at native abundance, non-target genotype controls, equal initial tumor burden, host/apoptosis strata, inhibitor-resistant alleles, barcode collision and rare-clone detection controls, matched cessation eligibility", "supporting_result": "Independent native models and baseline patient strata show driver-specific regression, while identified modifiers explain most initial failures and residual survival; selective residual-dependency correction adds sustained treatment-free control", "falsifying_result": "Fully verified selective withdrawal leaves substantial bulk tumors unchanged across baseline-defined pairs, or restored driver cannot reverse a purported withdrawal effect; residual populations recur despite candidate rescue and elimination controls" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Measure native driver activity and engagement in each surviving compartment, separating kinase function from entire-protein dependence.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Resolve whether reversible survivors arise before treatment, during exposure or by rare-clone selection using calibrated barcode and mutation-detection limits.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Prospectively map primary nonresponse within each baseline genotype pair rather than retrospectively defining addiction by response.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Separate true bypass from transgene reactivation, inadequate pharmacology and persistent wild-type pathway flux.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Establish the frequency of single-driver dependence across a representative pan-cancer maintenance denominator.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 6", "statement": "Test reservoir-specific loss and matched restoration with endogenous lineage-resolved relapse rather than culture viability alone.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 7", "statement": "Validate residual-state interventions in independent autochthonous models with dose, host and toxicity controls.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 8", "statement": "Distinguish preclinical immune-dependent complete responses from controlled clinical treatment-free cure.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 9", "statement": "Define cessation eligibility and sensitive residual assays prospectively; long-term molecular negativity does not prove absolute zero cells.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 10", "statement": "Audit inaccessible bodies, linked errata and supplements before claiming complete-paper review or transferring detailed control claims to the website.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-08", "reviewer": "Codex", "evidence_base_note": "66 primary reports; literature cutoff 2026-10-08; source examination UTC date 2026-10-09; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/Entrez; attempted Europe PMC XML and successful public NCBI PMC direct HTTPS access are separately logged. Signed-in Consensus browser discovery and targeted indexed full-text checks are reconciled with original sections; failed matches and source substitutions remain explicit. Zero Consensus API calls. SciSpace discovery was also used; matched primary leads were resolved to original records before counting. See scispace-leads.json.", "skill_version": "5.3", "validator_run": "exact archived v5.3 validator 2.3; see validator.txt", "validator_warnings_addressed": "Phenomenon entry was restated as the preregistered causal claim. No real phenomenon is labelled refuted; warning is explicitly justified.", "consensus_consistency_audit": "2026-10-09; supplementary provenance/source reconciliation; original grading retained; prior grades visible." }, "is_calibration_entry": { "value": false, "entry_role": "not_calibration", "blind_graded": null, "completed_blinded_calibration": false, "expected_band_sealed_at": "", "target_sha256": "", "target_authorship": "not applicable", "target_author_saw_review": null, "future_run_status": "not prepared", "unblinded_reason": "Ranking categorical verdict and index guidance were visible. No completed blinded calibration claimed." }, "upper_ladder_check": { "final_level_below_zeta": false, "equivalents_considered": [ { "kind": "mendelian_randomization", "available": false, "why_not_sufficient": "Genetic switches, native common-conduit inhibition, resistant-target reconstruction, genotype-defined treatment cohorts and recurrence/cessation tests are available upper-ladder routes. No RCT-only rule is imposed. They support Η for defined maintenance pairs, but do not remove major nonresponse and residual-cell exceptions or establish necessity and sufficiency across scope." }, { "kind": "natural_experiment", "available": false, "why_not_sufficient": "Genetic switches, native common-conduit inhibition, resistant-target reconstruction, genotype-defined treatment cohorts and recurrence/cessation tests are available upper-ladder routes. No RCT-only rule is imposed. They support Η for defined maintenance pairs, but do not remove major nonresponse and residual-cell exceptions or establish necessity and sufficiency across scope." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "Genetic switches, native common-conduit inhibition, resistant-target reconstruction, genotype-defined treatment cohorts and recurrence/cessation tests are available upper-ladder routes. No RCT-only rule is imposed. They support Η for defined maintenance pairs, but do not remove major nonresponse and residual-cell exceptions or establish necessity and sufficiency across scope." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Genetic switches, native common-conduit inhibition, resistant-target reconstruction, genotype-defined treatment cohorts and recurrence/cessation tests are available upper-ladder routes. No RCT-only rule is imposed. They support Η for defined maintenance pairs, but do not remove major nonresponse and residual-cell exceptions or establish necessity and sufficiency across scope." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": false, "why_not_sufficient": "Genetic switches, native common-conduit inhibition, resistant-target reconstruction, genotype-defined treatment cohorts and recurrence/cessation tests are available upper-ladder routes. No RCT-only rule is imposed. They support Η for defined maintenance pairs, but do not remove major nonresponse and residual-cell exceptions or establish necessity and sufficiency across scope." } ], "convergence_present": true, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 66, "claims_total": 70, "claims_verified": 70, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 66, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "Conditional MYC in hematopoietic lineages yields tumors that regress after transgene inactivation. Forced expression is not native human dosage; the abstract does not establish elimination of every residual cell or all sporadic tumors.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C2", "text": "Conditional H-RAS withdrawal regresses INK4a-null melanoma; enforced VEGF does not sustain the tumor after withdrawal. Engineered induction and genotype constrain scope; vascular effects do not establish universal tumor dependence.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C3", "text": "Suppressing conditional BCR-ABL1 reverses acute B-cell leukemia, with repeated induction and remission cycles. This mouse acute B-cell leukemia is not human chronic myeloid leukemia; repeat reversibility is not proven sterilization.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C4", "text": "Neu withdrawal regresses mammary tumors and pulmonary metastases to undetectability, but most animals later recur with Neu-independent tumors. Undetectable burden is not absence of residual cells; body controls were unavailable for examination.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C5", "text": "Both EGFR transgene withdrawal and erlotinib during continued doxycycline regress mutant-EGFR tumors; placebo and KRAS tumors fail the drug response. Transgene RNA is strongly induced and bulk protein is several-fold elevated; custom mouse MRI response and mostly normal histology do not establish eradication or physiological dosage.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph22, 0:Publisher HTML paragraphs:paragraph23, 0:Publisher HTML paragraphs:paragraph24, 0:Publisher HTML paragraphs:paragraph34, 0:Publisher HTML paragraphs:paragraph36, 0:Publisher HTML paragraphs:paragraph45, 0:Publisher HTML paragraphs:paragraph47, 0:Publisher HTML paragraphs:paragraph50, 0:Publisher HTML paragraphs:paragraph64, 0:Publisher HTML paragraphs:paragraph73. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C6", "text": "Brief MYC withdrawal in osteosarcoma promotes differentiation and sustained loss of neoplastic behavior despite later reactivation. This differentiation response is lineage specific and cannot establish treatment-free cure in every baseline driver pair.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C7", "text": "Genomically complex MYC lymphomas often regress after MYC inactivation; some escape with further chromosomal changes. The engineered lymphoma lineage and heterogeneous escape preclude universal dependence or cure.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C8", "text": "MYC withdrawal in liver tumors induces differentiation and dormancy; reactivation restores neoplastic properties in genetically related cells. Persistence is compatible with bulk addiction, and the abstract alone does not resolve every residual-cell dependency or reservoir-specific intervention.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C9", "text": "p53 deficiency impairs sustained MYC-withdrawal regression; p53 or thrombospondin restoration restores the response in the studied setting. Thrombospondin alone is insufficient; genotype and vascular mechanisms modify dependence rather than prove all-cancer withdrawal sufficiency.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C10", "text": "CD4 immunity and thrombospondin contribute to sustained regression after MYC or BCR-ABL inactivation. Host-dependent sustained control differs from immediate cell-autonomous collapse; linked erratum details were not examined.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C11", "text": "Conditional oncogenic Kras withdrawal regresses pancreatic lesions and changes the associated stroma. The engineered pancreas and p53 settings cannot establish all sporadic pancreatic tumors or residual-cell elimination.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C12", "text": "Switching off an endogenous conditional KRAS fusion allele regresses pancreatic tumors. The switch remains an engineered fusion and genotype-specific test; a linked author-name correction does not add an independent causal experiment.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C13", "text": "Dual MYC and KRAS mammary tumors regress more strongly when both are removed; recurrent tumors can reactivate inducible transgenes through rtTA mutations. Reactivation is different from verified driver-independent bypass; the result contests one-node generalization rather than proving every recurrent mechanism.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C14", "text": "MYC and KRAS withdrawal effects differ between lung tumors and lymphomas; dual withdrawal exceeds MYC-only lung responses. Cooperating pathways and tissue context preclude a uniform one-oncogene rule.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C15", "text": "BIM or PUMA loss reduces apoptosis and slows HER2-withdrawal regression; PUMA loss also impairs EGFR-withdrawal lung regression. Constitutive AKT/MEK separates downstream apoptotic routes. Apoptotic competence modifies response, and these inducible models do not show that every residual cell must depend on the driver.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph0, 1:RESULTS:paragraph1, 1:RESULTS:paragraph2, 1:RESULTS:paragraph6, 1:RESULTS:paragraph7, 1:RESULTS:paragraph8. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C16", "text": "Fate-labeled MYC lymphoma cells undergo arrest, differentiation and apoptosis after MYC withdrawal. A selected engineered lymphoma is not a representative pan-cancer dependency survey.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C17", "text": "Omomyc inhibition of endogenous MYC regresses KRAS-driven lung tumors with reversible effects on normal regenerative tissues. MYC is a downstream common conduit rather than the mutated initiating KRAS itself; later work shares the model family.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C18", "text": "Repeated four-week Omomyc on/off cycles lower KRAS-lung tumor recurrence; after eight cycles, three of four mice have no scored tumors after four weeks off. Refractory lesions suppress Omomyc expression. All animals recur after a first cycle; the final off-treatment cohort is small, histology excludes atypical hyperplasia, and four weeks is not lifelong sterile eradication. Linked erratum details remain unexamined.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 18 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph14, 0:Publisher HTML paragraphs:paragraph15, 0:Publisher HTML paragraphs:paragraph18, 0:Publisher HTML paragraphs:paragraph19, 0:Publisher HTML paragraphs:paragraph20, 0:Publisher HTML paragraphs:paragraph25, 0:Publisher HTML paragraphs:paragraph28, 0:Publisher HTML paragraphs:paragraph32, 0:Publisher HTML paragraphs:paragraph34, 0:Publisher HTML paragraphs:paragraph35. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C19", "text": "Lung-specific transgenic EML4-ALK tumors respond to an ALK inhibitor in the experimental mouse setting. Forced expression and transformation assays do not by themselves establish a native universal maintenance dependence.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C20", "text": "EML4-ALK fusions are identified in human lung tumors and transform experimental cells. Discovery and transformation capacity do not test continued native tumor maintenance.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C21", "text": "The selective ABL inhibitor suppresses CML colony formation while largely preserving normal hematopoietic growth. Colony suppression is not elimination of quiescent leukemic stem cells or an in vivo maintenance intervention.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C22", "text": "In phase 1 CML testing, 53 of 54 patients receiving at least 300 mg daily obtain complete hematologic response. Dose-cohort selection, nonrandomization and hematologic response do not establish cure or an all-dose response.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C23", "text": "IRIS randomizes 1106 CML patients and shows better cytogenetic response and progression control with imatinib than interferon plus cytarabine. Crossover complicates survival inference; drug treatment does not equal genetic removal or residual-cell eradication.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C24", "text": "EGFR kinase mutations associate with gefitinib response and show functional inhibitor sensitivity. The discovery comparison selects responders and nonresponders after outcome; it is not a prospective genotype-enrolled response denominator.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C25", "text": "EGFR mutations associate with inhibitor-sensitive lung cancer and alter drug-sensitive phosphorylation in experimental systems. Outcome-based discovery and smoking-history enrichment do not establish response in every prospectively defined mutation-positive tumor.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C26", "text": "In IPASS, gefitinib favors progression control in the mutation-positive subgroup and disadvantages mutation-negative patients relative to chemotherapy. Enrollment uses clinical features rather than EGFR genotype, and the molecular analysis is a tested subsample; subgroup estimates are not the entire enrolled cohort.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C27", "text": "Baseline EGFR-mutant NEJ002 enrollment yields 73.7 percent response and 10.8-month median progression-free survival with gefitinib, versus 30.7 percent and 5.4 months with chemotherapy. Responses are not universal; reported overall-survival comparison is not statistically decisive, and recurrence remains compatible with bulk addiction.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C28", "text": "FLAURA randomizes 556 baseline EGFR-mutant patients; osimertinib improves progression-free survival relative to active first-generation EGFR inhibitors. Both arms inhibit the same driver, so this comparison does not isolate inhibition versus none; initial response is not eradication.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C29", "text": "Later FLAURA analysis reports median overall survival of 38.6 versus 31.8 months. This is follow-up of the same 556-patient trial, not independent confirmation; survival benefit is not proof of sterile cure.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C30", "text": "HER2-selected metastatic breast cancer shows greater response and longer survival with trastuzumab plus chemotherapy than chemotherapy alone. Antibody-mediated immunity and chemotherapy contribute; this is not pure selective kinase withdrawal, and many tumors do not respond.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C31", "text": "BRIM-3 enrolls 675 baseline BRAF-mutant melanoma patients; vemurafenib yields 48 percent response versus 5 percent with dacarbazine and improves early survival. More than half lack an objective response in this report; the baseline genotype pair cannot be narrowed to responders after outcome.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C32", "text": "PROFILE 1007 enrolls 347 ALK-positive previously treated patients and improves response and progression-free survival with crizotinib versus chemotherapy. Interim overall survival is not significantly different; a linked erratum was not audited, and the outcome is not cure.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C33", "text": "PROFILE 1014 enrolls 343 untreated ALK-positive patients and improves response and progression-free survival with crizotinib versus chemotherapy. Crossover and immature survival limit causal survival claims; linked correction details remain unexamined.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C34", "text": "ALEX enrolls 303 ALK-positive patients and shows better progression and CNS control with alectinib than crizotinib. Two active ALK agents are compared; this is not a driver-off versus driver-on test or a treatment-free endpoint.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C35", "text": "CROWN enrolls 296 ALK-positive patients and improves response and progression control with lorlatinib versus crizotinib. Both arms inhibit ALK; toxicity and ongoing treatment remain, and later reports reuse this cohort.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C36", "text": "Five-year CROWN follow-up reports 60 percent versus 8 percent progression-free survival. Post hoc long follow-up of the same 296 patients is not a new trial or treatment-free eradication.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C37", "text": "Seven-year CROWN follow-up reports 55 percent versus 3 percent progression-free survival; overall survival remains immature. Durable control occurs on treatment and does not prove cure; neither is relapse inevitable by seven years for every patient. The same CROWN cohort is reused.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C38", "text": "Resistant CML samples contain ABL gatekeeper mutations or amplification; reconstructed mutant kinase resists imatinib. Drug resistance with restored signaling supports continuing target dependence, not independence after successful blockade; nine selected resistant cases do not define population frequency.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C39", "text": "T790M appears in three of six progressing EGFR-inhibitor cases; independent RFLP and matched mutant constructs support reduced drug-sensitive phosphorylation. One pretreatment sample is scant; sequencing sensitivity cannot exclude rare pre-existing cells. Cell-line viability contrasts have other background differences.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph15, 2:Results:paragraph16, 2:Results:paragraph17, 2:Results:paragraph18, 2:Results:paragraph19, 2:Results:paragraph26, 2:Results:paragraph29, 2:Results:paragraph31, 2:Results:paragraph32, 2:Results:paragraph34. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C40", "text": "MET amplification activates ERBB3-mediated bypass; combined MET and EGFR inhibition restores response in resistant cells, with amplification in four of eighteen resistant patients. Culture rescue and selected progressing biopsies do not establish universal clinical bypass frequency or durable cure.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C41", "text": "Combined irreversible EGFR inhibition and cetuximab regresses resistant EGFR-mutant mouse tumors and lowers receptor signaling and abundance more effectively than either alone. Combination activity includes antibody and abundance effects; the model does not establish efficacy in every human resistance state.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C42", "text": "Repeat biopsies from 37 progressing EGFR-mutant cancers retain EGFR mutations while showing heterogeneous mechanisms, including five small-cell transformations. This selected progression cohort is not all treated patients; retained mutation does not itself prove the new lineage remains EGFR-dependent.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C43", "text": "BRAF-mutant colon models resist BRAF inhibition through EGFR feedback; combined inhibition restores response, and ectopic EGFR can confer resistance in melanoma cells. The same driver behaves differently by tissue; experimental combination rescue does not prove all baseline BRAF tumors share one maintenance rule.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C44", "text": "ALK resistance biopsies and functional tests identify inhibitor-dependent spectra of secondary mutations and bypass sensitivity. Progressor selection and the shared clinical programme limit population estimates and independence; response after resistance is context specific.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C45", "text": "Experimental ALK selection and serial patient specimens show sequential compound mutations during inhibitor exposure. Ba/F3 selection and selected progressing samples cannot establish that all resistance follows this genetic route.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C46", "text": "Exploratory lorlatinib analysis links baseline secondary ALK mutations after prior inhibitors to higher response rates in tissue and plasma subgroups. This is a biomarker association within a treated phase-2 programme, not a randomized genotype intervention or an independent trial for each assay.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C47", "text": "Snail expression promotes recurrent mammary tumor behavior after Neu withdrawal and relates to a mesenchymal recurrence phenotype. Forced Snail gain does not establish native necessity of Snail in every residual tumor.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C48", "text": "Kras withdrawal initially regresses Kras/Mad2 lung tumors, followed by frequent recurrence with mostly absent oncogenic Kras transgene re-expression. The present case examines the abstract; original-body credit belongs to the preceding genome-instability review. Recurrence and aneuploidy do not directly prove a persister lineage or zero remaining instability.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C49", "text": "After Kras withdrawal, pancreatic tumors regress and twenty of twenty-eight recur; a subset lacks transgene signaling. YAP gain substitutes for Kras, while YAP/TEAD loss or binding-defective controls suppress bypass growth. About half reactivate the transgene through rtTA amplification; basal wild-type RAS remains. Relapse YAP-amplification and the engineered line constrain universal bypass claims; linked erratum details are unaudited.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph0, 1:RESULTS:paragraph1, 1:RESULTS:paragraph2, 1:RESULTS:paragraph3, 1:RESULTS:paragraph4, 1:RESULTS:paragraph5, 1:RESULTS:paragraph6, 1:RESULTS:paragraph8, 1:RESULTS:paragraph9, 1:RESULTS:paragraph16. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C50", "text": "KRAS-mutant cancer cell lines differ in KRAS dependency and epithelial state after RNA interference. Cell survival screens do not establish representative native tumor maintenance; a linked correction was not audited.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C51", "text": "Rare PC9 persisters survive concentrations far above drug IC50 with EGFR suppression; single-cell clones regenerate tolerance, withdrawal restores sensitivity, and KDM5A/HDAC/IGF1R controls separate reversible states from later T790M colonies. Cell-line state switching does not establish every patient reservoir; expanded persisters reverse more slowly, and pharmacologic prevention is not clinical treatment-free cure.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C52", "text": "CML stem/progenitor cultures survive strong BCR-ABL inhibition with cytokine support; phospho-CRKL/STAT5 controls, persistent inhibition and mostly Philadelphia-positive survivors address failed engagement or normal-cell carryover. Residual phospho-signal is not literally zero activity; culture cytokines and short exposure do not prove all in vivo stem cells are wholly driver independent or dispensability of the entire BCR-ABL protein.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph13, 0:Publisher HTML paragraphs:paragraph15, 0:Publisher HTML paragraphs:paragraph16, 0:Publisher HTML paragraphs:paragraph21, 0:Publisher HTML paragraphs:paragraph23, 0:Publisher HTML paragraphs:paragraph24, 0:Publisher HTML paragraphs:paragraph25, 0:Publisher HTML paragraphs:paragraph30, 0:Publisher HTML paragraphs:paragraph31, 0:Publisher HTML paragraphs:paragraph47, 0:Publisher HTML paragraphs:paragraph58. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C53", "text": "Quiescent Philadelphia-positive CML progenitors survive short imatinib culture exposure. Without matched complete target-engagement and niche controls, survival alone cannot distinguish insufficient inhibition from signaling-independent persistence.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C54", "text": "Barcoding, early resistant clones, persister pools and spiked-clone kinetic controls distinguish pre-existing and later T790M routes. Late-route cells resist apoptosis despite similar EGFR/ERK inhibition; navitoclax restores death and tumor response. Human line-response correlations do not trace original patient clones; low-frequency pretreatment mutations have detection limits, and the later route is not the only clinical route.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C55", "text": "Reversible persisters selectively depend on GPX4; knockout, ferrostatin rescue and iron/lipid controls identify ferroptotic death. Unmasking GPX4 deletion after tumor shrinkage prevents relapse in the tested melanoma xenograft. The in vivo intervention is genetic because compounds lack systemic bioavailability; continued targeted treatment, one xenograft and absent clinical safety testing do not establish treatment-free human cure.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 3:Main text:paragraph0, 3:Main text:paragraph2, 3:Main text:paragraph3, 3:Main text:paragraph4, 3:Main text:paragraph6, 3:Main text:paragraph7, 3:Main text:paragraph8. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C56", "text": "Barcoded cycling persister lineages show distinct antioxidant and fatty-acid-oxidation requirements under EGFR inhibition, with related states in human residual samples. Culture lineage dynamics and patient transcriptional resemblance do not quantify every patient's persister fraction or prove all clinical recurrence is state driven.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C57", "text": "APOBEC3A loss reduces treatment-associated mutagenesis and delays resistance in the experimental systems. Delay does not establish a sole universal resistance mechanism or spontaneous cancer initiation by APOBEC.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C58", "text": "FAK-YAP inhibition with EGFR inhibitors reduces residual disease and improves tumor response in tested experimental systems. Combined intervention and selected models do not establish a safe or universally curative clinical regimen.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C59", "text": "Residual and baseline tumors in an EGFR-mutant lung adenocarcinoma PDX retain genomic clonal architecture; rare baseline cells have DTP-like transcripts, and CAF populations shift toward IL6 production with in vitro CAF-state conversion. A single PDX, association and state similarity do not prove all patient reservoirs or native relapse dependency; linked correction details are unaudited.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 59 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C60", "text": "TROP2 derepression accompanies EGFR-inhibitor persisters; experimental TROP2-directed combination delays relapse, with preliminary phase-2 observations. Preliminary nonrandomized observations are not controlled treatment-free cure or universal residual-cell dependence.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C61", "text": "STIM tests stopping imatinib after at least two years of deep molecular remission; many relapse, while a selected fraction maintains molecular remission off treatment and relapsers respond to rechallenge. Enrollment selects prior deep responders, not all newly diagnosed CML; persistent molecular remission is not proof of absence of all leukemic cells. It contradicts continuous-drug necessity for every patient.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 61 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C62", "text": "Genome-scale CRISPR selection identifies diverse genes whose loss confers vemurafenib resistance. One cellular resistance screen is not a representative pan-cancer tumor-maintenance map or proof of one dominant oncogene across most cancers.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 62 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C63", "text": "NRAS melanoma RAS-on response and resistance depend on alterations including cyclophilin-A and MAP2K1; two clinical cases show divergent response. Two cases do not define response frequency or clinical cure. The peer-reviewed report replaces its earlier preprint without double counting.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 63 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C64", "text": "RAS-on inhibitor combinations regress tested tumors and require host T cells for deeper responses. These are preclinical results, not demonstrated regression or complete responses in NSCLC patients; host dependence limits purely cell-autonomous interpretation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 64 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C65", "text": "Acquired EML4-ALK restores wild-type RAS signaling under KRAS-G12C inhibition; continued KRAS blockade creates a context-specific ALK sensitivity and schedule-dependent combination response. Selected models and treatment sequence do not establish population prevalence or clinical eradication.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 65 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C66", "text": "RAS-on inhibition regresses pancreatic tumors in tested models; T cells and dendritic cells are required for the deeper response, with greater complete responses after immune combination. Complete responses are preclinical and combination dependent; shared drug-class programmes are not independent clinical validation or treatment-free cure.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 66 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC1", "text": "Η is supported for the prospectively named maintenance/regression pairs by endogenous conditional KRAS and MYC interventions, orthogonal EGFR withdrawal/drug controls, resistance alleles and several molecularly enrolled randomized trial families. This means causal regression in defined settings, not every enrolled tumor responding or every tumor cell requiring the driver. Nonresponse and context-specific bypass are major exceptions, preventing Θ and Ω.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 48, 49, 50, 51, 52, 53, 54, 61, 63, 64, 65, 66 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC2", "text": "Experimental dual-driver and tissue comparisons, heterogeneous KRAS cell dependency and genome-wide resistance screens show context dependence. These reports do not constitute a representative native pan-cancer maintenance map establishing a single dominant dependency in most cancers. The broad model has mechanistic plausibility, but its prespecified denominator and matching causal test are missing.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 13, 14, 17, 43, 50, 62 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC3", "text": "Initial regression and prolonged progression-free survival differ from eradication. Target-engaged human stem-cell survival, reversible tolerance, late resistance, transgene-independent recurrence and responder-selected treatment cessation contradict universal residual-cell elimination. Selected osteosarcoma differentiation or four-week off-treatment tumor absence after repeated Omomyc does not establish general lifelong cure.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 1, 3, 4, 5, 6, 7, 8, 9, 10, 13, 15, 18, 21, 28, 29, 34, 35, 36, 37, 39, 40, 41, 42, 44, 45, 46, 47, 48, 49, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CH", "text": "Defined driver–tumor pairs show strong oncogene dependence for regression; this does not establish one-driver addiction across most cancers or eradication of every residual cell.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 12, 5, 23, 27, 31, 33, 52, 61 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-09", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Felsher DW, Bishop JM et al. Reversible tumorigenesis by MYC in hematopoietic lineages. Molecular cell. 1999.", "tier": "A", "kind": "primary", "pmid": "10488335", "doi": "10.1016/s1097-2765(00)80367-6", "url": "https://pubmed.ncbi.nlm.nih.gov/10488335/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID10488335", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C1", "CSC1", "CSC3" ] }, { "n": 2, "citation": "Chin L, Tam A, Pomerantz J et al. Essential role for oncogenic Ras in tumour maintenance. Nature. 1999.", "tier": "A", "kind": "primary", "pmid": "10440378", "doi": "10.1038/22788", "url": "https://pubmed.ncbi.nlm.nih.gov/10440378/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID10440378", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C2", "CSC1" ] }, { "n": 3, "citation": "Huettner CS, Zhang P, Van Etten RA et al. Reversibility of acute B-cell leukaemia induced by BCR-ABL1. Nature genetics. 2000.", "tier": "A", "kind": "primary", "pmid": "10615128", "doi": "10.1038/71691", "url": "https://pubmed.ncbi.nlm.nih.gov/10615128/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID10615128", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C3", "CSC1", "CSC3" ] }, { "n": 4, "citation": "Moody SE, Sarkisian CJ, Hahn KT et al. Conditional activation of Neu in the mammary epithelium of transgenic mice results in reversible pulmonary metastasis. Cancer cell. 2002.", "tier": "A", "kind": "primary", "pmid": "12498714", "doi": "10.1016/s1535-6108(02)00212-x", "url": "https://pubmed.ncbi.nlm.nih.gov/12498714/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID12498714", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C4", "CSC1", "CSC3" ] }, { "n": 5, "citation": "Politi K, Zakowski MF, Fan PD et al. Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors. Genes & development. 2006.", "tier": "A", "kind": "primary", "pmid": "16705038", "doi": "10.1101/gad.1417406", "url": "https://pubmed.ncbi.nlm.nih.gov/16705038/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID16705038", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph22, 0:Publisher HTML paragraphs:paragraph23, 0:Publisher HTML paragraphs:paragraph24, 0:Publisher HTML paragraphs:paragraph34, 0:Publisher HTML paragraphs:paragraph36, 0:Publisher HTML paragraphs:paragraph45, 0:Publisher HTML paragraphs:paragraph47, 0:Publisher HTML paragraphs:paragraph50, 0:Publisher HTML paragraphs:paragraph64, 0:Publisher HTML paragraphs:paragraph73. No complete-paper or supplement audit claimed.", "carries_claims": [ "C5", "CSC1", "CSC3", "CH" ] }, { "n": 6, "citation": "Jain M, Arvanitis C, Chu K et al. Sustained loss of a neoplastic phenotype by brief inactivation of MYC. Science (New York, N.Y.). 2002.", "tier": "A", "kind": "primary", "pmid": "12098700", "doi": "10.1126/science.1071489", "url": "https://pubmed.ncbi.nlm.nih.gov/12098700/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID12098700", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C6", "CSC1", "CSC3" ] }, { "n": 7, "citation": "Karlsson A, Giuriato S, Tang F et al. Genomically complex lymphomas undergo sustained tumor regression upon MYC inactivation unless they acquire novel chromosomal translocations. Blood. 2003.", "tier": "A", "kind": "primary", "pmid": "12517816", "doi": "10.1182/blood-2002-10-3091", "url": "https://pubmed.ncbi.nlm.nih.gov/12517816/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID12517816", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C7", "CSC1", "CSC3" ] }, { "n": 8, "citation": "Shachaf CM, Kopelman AM, Arvanitis C et al. MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature. 2004.", "tier": "A", "kind": "primary", "pmid": "15475948", "doi": "10.1038/nature03043", "url": "https://pubmed.ncbi.nlm.nih.gov/15475948/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID15475948", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C8", "CSC1", "CSC3" ] }, { "n": 9, "citation": "Giuriato S, Ryeom S, Fan AC et al. Sustained regression of tumors upon MYC inactivation requires p53 or thrombospondin-1 to reverse the angiogenic switch. 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Science (New York, N.Y.). 2007.", "tier": "A", "kind": "primary", "pmid": "17463250", "doi": "10.1126/science.1141478", "url": "https://pubmed.ncbi.nlm.nih.gov/17463250/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID17463250", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C40", "CSC1", "CSC3" ] }, { "n": 41, "citation": "Regales L, Gong Y, Shen R et al. Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer. The Journal of clinical investigation. 2009.", "tier": "A", "kind": "primary", "pmid": "19759520", "doi": "10.1172/JCI38746", "url": "https://pubmed.ncbi.nlm.nih.gov/19759520/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID19759520", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C41", "CSC1", "CSC3" ] }, { "n": 42, "citation": "Sequist LV, Waltman BA, Dias-Santagata D et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Science translational medicine. 2011.", "tier": "A", "kind": "primary", "pmid": "21430269", "doi": "10.1126/scitranslmed.3002003", "url": "https://pubmed.ncbi.nlm.nih.gov/21430269/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID21430269", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C42", "CSC1", "CSC3" ] }, { "n": 43, "citation": "Prahallad A, Sun C, Huang S et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012.", "tier": "A", "kind": "primary", "pmid": "22281684", "doi": "10.1038/nature10868", "url": "https://pubmed.ncbi.nlm.nih.gov/22281684/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID22281684", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C43", "CSC1", "CSC2" ] }, { "n": 44, "citation": "Gainor JF, Dardaei L, Yoda S et al. Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer. Cancer discovery. 2016.", "tier": "A", "kind": "primary", "pmid": "27432227", "doi": "10.1158/2159-8290.CD-16-0596", "url": "https://pubmed.ncbi.nlm.nih.gov/27432227/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID27432227", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C44", "CSC1", "CSC3" ] }, { "n": 45, "citation": "Yoda S, Lin JJ, Lawrence MS et al. Sequential ALK Inhibitors Can Select for Lorlatinib-Resistant Compound ALK Mutations in ALK-Positive Lung Cancer. Cancer discovery. 2018.", "tier": "A", "kind": "primary", "pmid": "29650534", "doi": "10.1158/2159-8290.CD-17-1256", "url": "https://pubmed.ncbi.nlm.nih.gov/29650534/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID29650534", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C45", "CSC1", "CSC3" ] }, { "n": 46, "citation": "Shaw AT, Solomon BJ, Besse B et al. ALK Resistance Mutations and Efficacy of Lorlatinib in Advanced Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2019.", "tier": "A", "kind": "primary", "pmid": "30892989", "doi": "10.1200/JCO.18.02236", "url": "https://pubmed.ncbi.nlm.nih.gov/30892989/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID30892989", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C46", "CSC1", "CSC3" ] }, { "n": 47, "citation": "Moody SE, Perez D, Pan TC et al. The transcriptional repressor Snail promotes mammary tumor recurrence. 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Nature. 2010.", "tier": "A", "kind": "primary", "pmid": "20173739", "doi": "10.1038/nature08803", "url": "https://pubmed.ncbi.nlm.nih.gov/20173739/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID20173739", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C48", "CSC1", "CSC3" ] }, { "n": 49, "citation": "Kapoor A, Yao W, Ying H et al. Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer. Cell. 2014.", "tier": "A", "kind": "primary", "pmid": "24954535", "doi": "10.1016/j.cell.2014.06.003", "url": "https://pubmed.ncbi.nlm.nih.gov/24954535/", "status_flags": [ "ErratumIn: PMID31730860" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID24954535", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph0, 1:RESULTS:paragraph1, 1:RESULTS:paragraph2, 1:RESULTS:paragraph3, 1:RESULTS:paragraph4, 1:RESULTS:paragraph5, 1:RESULTS:paragraph6, 1:RESULTS:paragraph8, 1:RESULTS:paragraph9, 1:RESULTS:paragraph16. No complete-paper or supplement audit claimed.", "carries_claims": [ "C49", "CSC1", "CSC3" ] }, { "n": 50, "citation": "Singh A, Greninger P, Rhodes D et al. A gene expression signature associated with \"K-Ras addiction\" reveals regulators of EMT and tumor cell survival. Cancer cell. 2009.", "tier": "A", "kind": "primary", "pmid": "19477428", "doi": "10.1016/j.ccr.2009.03.022", "url": "https://pubmed.ncbi.nlm.nih.gov/19477428/", "status_flags": [ "ErratumIn: PMID33689705" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID19477428", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C50", "CSC1", "CSC2" ] }, { "n": 51, "citation": "Sharma SV, Lee DY, Li B et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. 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The Journal of clinical investigation. 2011.", "tier": "A", "kind": "primary", "pmid": "21157039", "doi": "10.1172/JCI35721", "url": "https://pubmed.ncbi.nlm.nih.gov/21157039/", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID21157039", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph13, 0:Publisher HTML paragraphs:paragraph15, 0:Publisher HTML paragraphs:paragraph16, 0:Publisher HTML paragraphs:paragraph21, 0:Publisher HTML paragraphs:paragraph23, 0:Publisher HTML paragraphs:paragraph24, 0:Publisher HTML paragraphs:paragraph25, 0:Publisher HTML paragraphs:paragraph30, 0:Publisher HTML paragraphs:paragraph31, 0:Publisher HTML paragraphs:paragraph47, 0:Publisher HTML paragraphs:paragraph58. 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Nature. 2017.", "tier": "A", "kind": "primary", "pmid": "29088702", "doi": "10.1038/nature24297", "url": "https://pubmed.ncbi.nlm.nih.gov/29088702/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID29088702", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 3:Main text:paragraph0, 3:Main text:paragraph2, 3:Main text:paragraph3, 3:Main text:paragraph4, 3:Main text:paragraph6, 3:Main text:paragraph7, 3:Main text:paragraph8. No complete-paper or supplement audit claimed.", "carries_claims": [ "C55", "CSC3" ] }, { "n": 56, "citation": "Oren Y, Tsabar M, Cuoco MS et al. Cycling cancer persister cells arise from lineages with distinct programs. 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Nature communications. 2024.", "tier": "A", "kind": "primary", "pmid": "38702301", "doi": "10.1038/s41467-024-47423-0", "url": "https://pubmed.ncbi.nlm.nih.gov/38702301/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID38702301", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C58", "CSC3" ] }, { "n": 59, "citation": "Moghal N, Li Q, Stewart EL et al. Single-Cell Analysis Reveals Transcriptomic Features of Drug-Tolerant Persisters and Stromal Adaptation in a Patient-Derived EGFR-Mutated Lung Adenocarcinoma Xenograft Model. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2023.", "tier": "A", "kind": "primary", "pmid": "36535627", "doi": "10.1016/j.jtho.2022.12.003", "url": "https://pubmed.ncbi.nlm.nih.gov/36535627/", "status_flags": [ "ErratumIn: PMID37999691" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID36535627", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C59", "CSC3" ] }, { "n": 60, "citation": "Liao J, Yao W, Yu Y et al. Targeting TROP2 in drug-tolerant persister cells delays EGFR tyrosine kinase inhibitor resistance in non-small-cell lung cancer. 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Oncology. 2010.", "tier": "A", "kind": "primary", "pmid": "20965785", "doi": "10.1016/S1470-2045(10)70233-3", "url": "https://pubmed.ncbi.nlm.nih.gov/20965785/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID20965785", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C61", "CSC1", "CSC3", "CH" ] }, { "n": 62, "citation": "Shalem O, Sanjana NE, Hartenian E et al. Genome-scale CRISPR-Cas9 knockout screening in human cells. 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Cancer discovery. 2026.", "tier": "A", "kind": "primary", "pmid": "42329099", "doi": "10.1158/2159-8290.CD-25-0477", "url": "https://pubmed.ncbi.nlm.nih.gov/42329099/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID42329099", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C65", "CSC1", "CSC3" ] }, { "n": 66, "citation": "Orlen M, Vostrejs WP, Sor R et al. T-cell Dependency of Tumor Regressions and Complete Responses with RAS(ON) Multi-selective Inhibition in Preclinical Models of Pancreatic Ductal Adenocarcinoma. Cancer discovery. 2025.", "tier": "A", "kind": "primary", "pmid": "40057911", "doi": "10.1158/2159-8290.CD-24-1475", "url": "https://pubmed.ncbi.nlm.nih.gov/40057911/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID40057911", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C66", "CSC1", "CSC3" ] } ], "independence_basis": { "required": true, "lines": [ { "label": "Endogenous conditional driver switch", "sources": [ 12 ], "excludes_error": "A native-locus conditional KRAS activity switch tests maintenance rather than mere transformed-cell sensitivity; its fusion and pancreas genotype remain limitations." }, { "label": "Native common-conduit dependence", "sources": [ 17, 18 ], "excludes_error": "Omomyc acts on endogenous MYC in KRAS-driven autochthonous tumors and measures recurrence; the two papers share the same model programme and form one line." }, { "label": "Orthogonal target withdrawal and engagement", "sources": [ 5, 15 ], "excludes_error": "EGFR genetic withdrawal and drug inhibition with continued induction and KRAS controls address drug nonspecificity; apoptotic-effector genetics map a different potential failure. Related inducible lines are grouped." }, { "label": "Target resistance reconstruction", "sources": [ 38, 39, 41 ], "excludes_error": "BCR-ABL and EGFR resistance alleles and complementary EGFR blockade distinguish loss of target inhibition from target independence; EGFR follow-up constructs share a programme." }, { "label": "Independent molecular clinical settings", "sources": [ 23, 27, 30, 31, 33, 34 ], "excludes_error": "Distinct CML, EGFR-lung, HER2-breast, BRAF-melanoma and ALK-lung trials address engineered-model artifact. Shared biomarker selection and drug specificity remain; active-inhibitor comparisons do not substitute for genetic withdrawal." }, { "label": "Functional bypass", "sources": [ 49, 43 ], "excludes_error": "YAP/TEAD withdrawal/rescue and BRAF tissue-specific EGFR feedback have different nodes, tissues and control failures; selected experimental models limit prevalence." }, { "label": "Dynamic persister mechanisms", "sources": [ 51, 54, 55 ], "excludes_error": "Single-cell reversible states and barcode/kinetic routes share some EGFR platforms. Independent GPX4 genetic/antioxidant controls and residual melanoma course test a distinct state-specific survival mechanism." } ], "shared_failure_mode_checked": true, "note": "Clinical follow-ups are grouped by trial, not by paper: FLAURA has two reports and CROWN three. MYC/Omomyc, inducible Neu, EGFR transgene, inducible pancreatic Kras, MGH serial-biopsy programmes and persister lineages have shared components. Distinct drug classes alone are not independence; genetic specificity, non-target genotype controls, native-locus switches and molecular human endpoints exclude partly different errors. The retained corpus has independent disease settings rather than 66 independent causal confirmations. Marinkovic/Wirth GFP-fate transplantation is a separate laboratory model and is not assigned to the Felsher MYC programme merely because both use conditional MYC." }, "consensus_validation": { "completed": true, "status": "documented_historical_discovery_and_reconciliation", "provider": "Consensus", "provider_mode": "Historical browser/connector use as recorded in the source artifacts", "local_audit_date": "2026-10-09", "primary_comparison_count": null, "reported_usage": [ { "path": "D:\\HypothesisCritic\\deliverables\\hsef_v53_popularity_ranks_36_40_2026-10-08\\oncogene-addiction\\consensus\\usage.json", "metrics": { "deep_queries": 0, "api_calls": 0, "browser_pro_queries": 2, "targeted_studies_requested": 8, "original_passage_comparisons": 1 } } ], "grade_changed": false, "score_before": { "hsef_level": "Η", "hsef_descriptor": "Strong convergent causal evidence, intervention-sensitive", "confidence": "Moderate", "confidence_rationale": "Multiple independent studies across several disease settings with partial replication, but methodological heterogeneity persists: many founding perturbations share model programmes, several clinical lines compare active inhibitors rather than driver-on versus driver-off, and control sets differ across assay classes. Evidence density and reproducibility set the Moderate band, not the reviewer's access depth and not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "The preregistered scope-matched rule reports SC1 at Η: endogenous conditional-driver and common-conduit interventions, genetic withdrawal, mechanistic resistance/rescue and baseline molecularly defined clinical trials converge on tumor-maintenance dependence across named pairs. Significant primary nonresponse, host/apoptosis dependence and persistence prevent Θ or Ω. SC2 pan-cancer one-driver generalization and SC3 residual-cell eradication remain Γ as broader mechanistic claims without matching general causal validation." }, "score_after": { "hsef_level": "Η", "hsef_descriptor": "Strong convergent causal evidence, intervention-sensitive", "confidence": "Moderate", "confidence_rationale": "Multiple independent studies across several disease settings with partial replication, but methodological heterogeneity persists: many founding perturbations share model programmes, several clinical lines compare active inhibitors rather than driver-on versus driver-off, and control sets differ across assay classes. Evidence density and reproducibility set the Moderate band, not the reviewer's access depth and not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "The preregistered scope-matched rule reports SC1 at Η: endogenous conditional-driver and common-conduit interventions, genetic withdrawal, mechanistic resistance/rescue and baseline molecularly defined clinical trials converge on tumor-maintenance dependence across named pairs. Significant primary nonresponse, host/apoptosis dependence and persistence prevent Θ or Ω. SC2 pan-cancer one-driver generalization and SC3 residual-cell eradication remain Γ as broader mechanistic claims without matching general causal validation." }, "independent_blinded_audit": false, "raw_receipts": [ { "path": "deliverables\\hsef_v53_popularity_ranks_36_40_2026-10-08\\oncogene-addiction\\consensus-anchors-search-log.json", "sha256": "64ce1aa64272d7998b58f19b64666b0d975ec34289fa581177281317159af959" }, { "path": "deliverables\\hsef_v53_popularity_ranks_36_40_2026-10-08\\oncogene-addiction\\consensus-anchors.json", "sha256": "b071f0bcc115e90ce219ed41e0d6fcaf433addcdade19947601b74709f803fcc" }, { "path": "deliverables\\hsef_v53_popularity_ranks_36_40_2026-10-08\\oncogene-addiction\\consensus\\broad-ax.txt", "sha256": "ecf1c27fd264b3682cbce92aa9c782b64f9ab80f5ee5be3e2693a5f9e4387e3e" }, { "path": "deliverables\\hsef_v53_popularity_ranks_36_40_2026-10-08\\oncogene-addiction\\consensus\\RECONCILIATION.md", "sha256": "525282c8473fdd140433542bfdc46ca31a6277c99267a78b7f791b684c11b9ac" }, { "path": "deliverables\\hsef_v53_popularity_ranks_36_40_2026-10-08\\oncogene-addiction\\consensus\\targeted-ax.txt", "sha256": "f329a8b2fbd9fef059363a9542477cdf85b4b0fcf0abb074f4c109856707d0cf" } ], "limitations": "This verifies documented historical use and links the record to the final edition. 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