{"entity":{"id":"paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011","kind":"paper","name":"Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors","aka":[],"tldr":"37 patients were re-biopsied when their EGFR drug stopped working. Some had the expected resistance mutation; five had turned into small-cell lung cancer. In three, the resistance disappeared when the drug was stopped.","summary":"Sequist, Waltman, Dias-Santagata and colleagues, with Engelman as senior author, performed systematic genetic and histological analysis of tumour biopsies from 37 patients with drug-resistant EGFR-mutant non-small-cell lung cancers.\n\nThree findings in one paper remade how resistance is thought about. Resistance is heterogeneous in mechanism; it can be histological rather than genetic, with 14 percent of tumours transforming into small-cell lung cancer; and it can be reversible, with resistance mechanisms lost when the selective pressure is removed, so that a patient can respond again to a drug they had already failed.","asOf":"2026-09-25","links":[{"label":"Sci Transl Med 2011","url":"https://doi.org/10.1126/scitranslmed.3002003"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/21430269/"},{"label":"Europe PMC","url":"https://europepmc.org/article/MED/21430269"}],"tags":["lung-evidence"],"related":["paper-kobayashi-egfr-t790m-gefitinib-resistance-nejm-2005","paper-tracerx-100-nejm-2017","paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019","egfr-t790m","met-amplification-readout","histologic-transformation","met-amplification"],"cancers":["lung-cancer","nsclc","egfr-mutant-nsclc","sclc"],"sections":["targeted-therapy","diagnostics"],"technologies":["ngs"],"targets":["egfr","met","rb1","tp53"],"drugs":["gefitinib","erlotinib","osimertinib"],"companies":[],"institutions":["mgh"],"pathways":["pi3k-akt-mtor","resistance-routes-map","lineage-plasticity-neuroendocrine","clonal-evolution"],"terms":["resistance","histology","clonal-evolution","histologic-transformation","biopsy"],"trials":[],"people":["lecia-sequist"],"bottlenecks":["b-resistance","b-tumor-heterogeneity","b-preclinical-models"],"keyPapers":[],"journals":["science-translational-medicine"],"dependsOn":[],"notes":[],"journal":"Science Translational Medicine","year":2011,"doi":"10.1126/scitranslmed.3002003","pmid":"21430269","authors":"Sequist LV, Waltman BA, Dias-Santagata D, et al.","paperType":"translational","findings":["All drug-resistant tumours retained their original activating EGFR mutations.","Known resistance mechanisms were found in some: the EGFR T790M mutation or MET gene amplification.","Unexpected changes included EGFR amplification and PIK3CA mutations","Five resistant tumours (14 percent) transformed from non-small-cell into small-cell lung cancer and were sensitive to standard small-cell treatments.","In three patients, serial biopsies showed genetic resistance mechanisms were lost without continued selective pressure, and those cancers responded again to EGFR inhibitors."],"whatItMeans":"The case for re-biopsy at progression, for treating resistance as a diagnosis rather than an endpoint, and for the idea of a drug holiday. It is also the origin of resistance-directed sequencing: what you give next should depend on what the tumour became.","caveats":["37 patients from one centre, biopsied when it was feasible, which selects for accessible disease.","Mechanisms were assigned from single-site biopsies, so heterogeneity between lesions in the same patient is invisible.","Reversibility was seen in three patients and has never been tested prospectively as a treatment strategy."],"changedPractice":true,"participants":37},"route":"/key-papers/paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011/","neighbours":{"paper":[{"id":"paper-kobayashi-egfr-t790m-gefitinib-resistance-nejm-2005","kind":"paper","name":"EGFR mutation and resistance of non-small-cell lung cancer to gefitinib","route":"/key-papers/paper-kobayashi-egfr-t790m-gefitinib-resistance-nejm-2005/"},{"id":"paper-mariposa-nejm-2024","kind":"paper","name":"MARIPOSA: amivantamab plus lazertinib versus osimertinib as first treatment for EGFR-mutated lung cancer","route":"/key-papers/paper-mariposa-nejm-2024/"},{"id":"paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019","kind":"paper","name":"Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data","route":"/key-papers/paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019/"},{"id":"paper-tracerx-100-nejm-2017","kind":"paper","name":"TRACERx first 100: tracking how lung cancers evolve, and how chromosomal chaos predicts relapse","route":"/key-papers/paper-tracerx-100-nejm-2017/"}],"biomarker":[{"id":"egfr-t790m","kind":"biomarker","name":"EGFR T790M","route":"/biomarkers/egfr-t790m/"},{"id":"met-amplification-readout","kind":"biomarker","name":"MET amplification (gene copy number)","route":"/biomarkers/met-amplification-readout/"}],"term":[{"id":"biopsy","kind":"term","name":"Biopsy","route":"/terms/biopsy/"},{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"},{"id":"histologic-transformation","kind":"term","name":"Histologic transformation","route":"/terms/histologic-transformation/"},{"id":"histology","kind":"term","name":"Histology","route":"/terms/histology/"},{"id":"met-amplification","kind":"term","name":"MET amplification (bypass resistance)","route":"/terms/met-amplification/"},{"id":"ngs","kind":"term","name":"Next-generation sequencing (NGS)","route":"/terms/ngs/"}],"cancer":[{"id":"egfr-mutant-nsclc","kind":"cancer","name":"EGFR-mutated non-small-cell lung cancer","route":"/cancers/egfr-mutant-nsclc/"},{"id":"lung-cancer","kind":"cancer","name":"Lung cancer (all types)","route":"/cancers/lung-cancer/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"},{"id":"sclc","kind":"cancer","name":"Small-cell lung cancer","route":"/cancers/sclc/"}],"section":[{"id":"diagnostics","kind":"section","name":"Diagnostics & Biomarkers","route":"/fronts/diagnostics/"},{"id":"targeted-therapy","kind":"section","name":"Targeted Therapy","route":"/fronts/targeted-therapy/"}],"target":[{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"met","kind":"target","name":"MET","route":"/targets/met/"},{"id":"rb1","kind":"target","name":"RB1","route":"/targets/rb1/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"drug":[{"id":"erlotinib","kind":"drug","name":"Erlotinib","route":"/drugs/erlotinib/"},{"id":"gefitinib","kind":"drug","name":"Gefitinib","route":"/drugs/gefitinib/"},{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"}],"institution":[{"id":"mgh","kind":"institution","name":"Massachusetts General Hospital Cancer Center","route":"/institutions/mgh/"}],"pathway":[{"id":"clonal-evolution","kind":"pathway","name":"Clonal evolution & minimal residual disease","route":"/pathways/clonal-evolution/"},{"id":"lineage-plasticity-neuroendocrine","kind":"pathway","name":"Lineage plasticity & neuroendocrine transformation","route":"/pathways/lineage-plasticity-neuroendocrine/"},{"id":"pi3k-akt-mtor","kind":"pathway","name":"PI3K / AKT / mTOR","route":"/pathways/pi3k-akt-mtor/"},{"id":"resistance-routes-map","kind":"pathway","name":"Resistance routes: how a blocked pathway comes back","route":"/pathways/resistance-routes-map/"}],"person":[{"id":"lecia-sequist","kind":"person","name":"Lecia V. Sequist","route":"/people/lecia-sequist/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-preclinical-models","kind":"bottleneck","name":"Lab models that fail to predict what happens in patients","route":"/bottlenecks/b-preclinical-models/"},{"id":"b-tumor-heterogeneity","kind":"bottleneck","name":"Tumour heterogeneity and clonal evolution","route":"/bottlenecks/b-tumor-heterogeneity/"}],"journal":[{"id":"science-translational-medicine","kind":"journal","name":"Science Translational Medicine","route":"/journals/science-translational-medicine/"}],"roadmap":[{"id":"lung-cancer-evidence-roadmap","kind":"roadmap","name":"Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch","route":"/roadmaps/lung-cancer-evidence-roadmap/"}],"idea":[{"id":"idea-lung-resistance-directed-sequencing-at-every-progression","kind":"idea","name":"Make resistance a diagnosis: sequence at every progression and choose the next line from what the tumour became","route":"/ideas/idea-lung-resistance-directed-sequencing-at-every-progression/"},{"id":"idea-lung-uk-screening-testing-and-access-gaps","kind":"idea","name":"Publish the four numbers the NHS lung cancer pathway does not currently measure: reflex testing rate, genomic turnaround, surgical access and a lung-specific waiting time in every nation","route":"/ideas/idea-lung-uk-screening-testing-and-access-gaps/"}]}}