# Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors

Source: https://onco.cc/key-papers/paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011/  
OnCo record `paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

Three 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.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Tags: lung-evidence
- Journal: Science Translational Medicine
- Year: 2011
- DOI: 10.1126/scitranslmed.3002003
- Authors: Sequist LV, Waltman BA, Dias-Santagata D, et al.
- 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.
- What it means: 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.

## Sources

- Sci Transl Med 2011: https://doi.org/10.1126/scitranslmed.3002003
- PubMed: https://pubmed.ncbi.nlm.nih.gov/21430269/

## Connected records

- key papers: [Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC](https://onco.cc/key-papers/paper-cho-mariposa-amivantamab-lazertinib-nejm-2024/), [EGFR mutation and resistance of non-small-cell lung cancer to gefitinib](https://onco.cc/key-papers/paper-kobayashi-egfr-t790m-gefitinib-resistance-nejm-2005/), [Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data](https://onco.cc/key-papers/paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019/), [Tracking the evolution of non-small-cell lung cancer](https://onco.cc/key-papers/paper-jamal-hanjani-tracerx-evolution-nsclc-nejm-2017/)
- cancers: [EGFR-mutated non-small-cell lung cancer](https://onco.cc/cancers/egfr-mutant-nsclc/), [Lung cancer (all types)](https://onco.cc/cancers/lung-cancer/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/), [Small-cell lung cancer](https://onco.cc/cancers/sclc/)
- fronts: [Diagnostics & Biomarkers](https://onco.cc/fronts/diagnostics/), [Targeted Therapy](https://onco.cc/fronts/targeted-therapy/)
- terms: [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [Histology](https://onco.cc/terms/histology/), [Next-generation sequencing (NGS)](https://onco.cc/terms/ngs/)
- targets: [EGFR](https://onco.cc/targets/egfr/), [MET](https://onco.cc/targets/met/)
- drugs: [Erlotinib](https://onco.cc/drugs/erlotinib/), [Gefitinib](https://onco.cc/drugs/gefitinib/), [Osimertinib](https://onco.cc/drugs/osimertinib/)
- institutions: [Massachusetts General Hospital Cancer Center](https://onco.cc/institutions/mgh/)
- pathways: [Clonal evolution & minimal residual disease](https://onco.cc/pathways/clonal-evolution/), [PI3K / AKT / mTOR](https://onco.cc/pathways/pi3k-akt-mtor/)
- people: [Lecia V. Sequist](https://onco.cc/people/lecia-sequist/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [Lab models that fail to predict what happens in patients](https://onco.cc/bottlenecks/b-preclinical-models/), [Tumour heterogeneity and clonal evolution](https://onco.cc/bottlenecks/b-tumor-heterogeneity/)
- journals: [Science Translational Medicine](https://onco.cc/journals/science-translational-medicine/)
- roadmaps: [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](https://onco.cc/roadmaps/lung-cancer-evidence-roadmap/)
- ideas: [Close the United Kingdom lung cancer gaps the UK page names: screening rollout, diagnostic pathway, molecular testing and drug access](https://onco.cc/ideas/idea-lung-uk-screening-testing-and-access-gaps/), [Make resistance a diagnosis: sequence at every progression and choose the next line from what the tumour became](https://onco.cc/ideas/idea-lung-resistance-directed-sequencing-at-every-progression/)

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