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Updated: Oct 17, 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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Evolution of MET and NRAS gene amplification as acquired resistance mechanisms in EGFR mutant NSCLC

T L Peters1, T Patil1, A T Le1

  • 1Department of Medicine, Division of Medical Oncology, University of Colorado- Anschutz Medical Campus, Aurora, CO, USA.

NPJ Precision Oncology
|October 13, 2021
PubMed

Insights

Acquired resistance in EGFR-mutant lung cancer is complex. Molecular testing identified NRAS amplification as a resistance mechanism, suggesting EGFR and MEK inhibitors may overcome this challenge.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Non-small cell lung cancer (NSCLC) with EGFR mutations initially responds to targeted therapies.
  • Acquired resistance to these treatments is a significant clinical challenge.
  • Understanding resistance mechanisms is key to developing effective treatment strategies.

Purpose of the Study:

  • To investigate the molecular mechanisms of acquired resistance in EGFR-mutant NSCLC.
  • To analyze resistance development through successive treatment stages in a patient.
  • To identify novel therapeutic targets for overcoming drug resistance.

Main Methods:

  • Performed comprehensive molecular testing on a patient with progressive NSCLC.
  • Utilized a patient-derived cell line to study resistance mechanisms.
  • Analyzed downstream signaling pathways including ERK and Akt.

Main Results:

  • Identified MET gene amplification as an early resistance mechanism to EGFR inhibitors.
  • Discovered NRAS gene amplification as a driver of resistance to combined EGFR and MET therapies.
  • Observed sustained extracellular signal-related kinase (ERK) activation due to NRAS amplification.
  • Demonstrated that trametinib (a MEK inhibitor) could eliminate ERK activation.

Conclusions:

  • NRAS gene amplification represents a novel mechanism of acquired resistance in EGFR-mutant NSCLC.
  • Targeting MEK with trametinib may be effective against NRAS-amplified, EGFR-mutant NSCLC.
  • Combination therapy with EGFR and MEK inhibitors shows promise for overcoming specific resistance patterns.

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