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Updated: Dec 9, 2025

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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Genomic Profiling Identifies Outcome-Relevant Mechanisms of Innate and Acquired Resistance to Third-Generation

Sebastian Michels1, Carina Heydt1, Bianca van Veggel2

  • 1University Hospital of Cologne, Cologne, Germany.

JCO Precision Oncology
|September 11, 2020
PubMed
Abstract

Insights

Third-generation EGFR TKIs show variable efficacy in EGFR-mutant lung cancer. MET amplification significantly reduces efficacy and is a common resistance mechanism, suggesting combination therapies may improve outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a key treatment for EGFR-mutant lung cancer with acquired resistance (AR) to earlier TKIs.
  • However, patient responses to these advanced TKIs exhibit significant interindividual variability.

Purpose of the Study:

  • To investigate the molecular profiles of pretreatment and post-treatment samples from patients with EGFR-mutant lung cancer.
  • To determine the impact of these molecular characteristics on treatment outcomes with third-generation EGFR TKIs.

Main Methods:

  • Molecular characterization of 124 patients with EGFR p.T790M-positive AR to early-generation EGFR TKIs.
  • Correlative analyses of treatment outcomes and molecular profiles in 56 patients.
  • Analysis of post-treatment biopsy samples from 29 patients who progressed on third-generation EGFR TKIs.

Main Results:

  • Co-occurring genetic aberrations were identified in 74.4% of EGFR p.T790M-positive samples.
  • TP53 mutations were frequent (44.5%) but did not significantly impact treatment.
  • MET amplification (5% of samples) was associated with significantly reduced efficacy (median PFS 1.0 months vs. 8.2 months).
  • Mechanisms of acquired resistance to third-generation TKIs included EGFR alterations (e.g., p.T790M loss, p.C797S, p.G724S acquisition) and other gene changes (e.g., MET amplification, KRAS mutations).

Conclusions:

  • Frequent additional genetic aberrations in EGFR-mutant lung cancer can mediate resistance to third-generation EGFR TKIs.
  • MET amplification is strongly linked to primary treatment failure and is a common mechanism of acquired resistance.
  • Combining EGFR inhibitors with TKIs targeting resistance mechanisms may help delay acquired resistance and improve patient outcomes.

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