Related Experiment Video

Updated: Mar 20, 2026

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure

Published on: August 11, 2017

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Heterogeneous Mechanisms of Primary and Acquired Resistance to Third-Generation EGFR Inhibitors

Sandra Ortiz-Cuaran1, Matthias Scheffler2, Dennis Plenker3

  • 1Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, Germany.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|June 3, 2016
PubMed
Abstract

Insights

Third-generation EGFR inhibitors face resistance via MET or ERBB2 amplification and KRAS mutations in lung adenocarcinoma. Combination therapies like EGFR/MEK inhibition show promise for overcoming resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Lung adenocarcinoma is a leading cause of cancer death.
  • Epidermal growth factor receptor (EGFR) inhibitors are crucial therapies.
  • Resistance to third-generation EGFR inhibitors necessitates understanding novel resistance mechanisms.

Purpose of the Study:

  • To identify novel mechanisms of resistance to third-generation EGFR inhibitors (AZD9291, rociletinib).
  • To investigate resistance in lung adenocarcinoma patients progressing on these therapies.

Main Methods:

  • Analysis of tumor biopsies from seven patients (pre-, during, post-treatment).
  • Utilized targeted sequencing and FISH analyses.
  • Functional assessment of candidate genes in in vitro models.

Main Results:

  • Recurrent MET or ERBB2 amplification identified in resistant tumors.
  • MET and ERBB2 activation confer resistance to third-generation EGFR inhibitors.
  • A KRASG12S mutation was identified as a potential driver of acquired resistance to AZD9291.
  • Dual EGFR/MEK inhibition showed potential to overcome resistance in EGFR-mutant cells with mutant KRAS.

Conclusions:

  • Heterogeneous mechanisms drive primary and acquired resistance to third-generation EGFR inhibitors.
  • Findings provide a rationale for combination therapeutic strategies.
  • Dual inhibition strategies may overcome resistance in specific patient subsets.

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