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Updated: Jul 2, 2026

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
09:38

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

MET Dependence Oversteps EGFR Dependence via Balancing Dimerization of the Receptor Tyrosine Kinases in

Yuri Yagami1, Takashi Sato1, Hiroki Yamamoto1

  • 1Department of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara, Japan.

Thoracic Cancer
|July 1, 2026
PubMed
Abstract

Insights

MET amplification in EGFR-mutated non-small cell lung cancer (NSCLC) shifts signaling dependence from EGFR to MET, impacting resistance to tyrosine kinase inhibitors (TKIs). This provides insights for developing new TKI therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) improve outcomes for EGFR-mutated non-small cell lung cancer (NSCLC).
  • Acquired resistance is a major challenge, with MET amplification being a common mechanism.
  • The precise impact of MET amplification on receptor dimerization and signaling dependence remains unclear.

Purpose of the Study:

  • To investigate the effects of MET amplification on EGFR/MET/ERBB3 signaling and dimerization in acquired resistance to EGFR-TKIs.
  • To evaluate the therapeutic potential of MET tyrosine kinase inhibitors (MET-TKIs) in this context.

Main Methods:

  • Established an osimertinib-resistant NSCLC cell line (HCC827OR) with MET amplification.
  • Analyzed receptor tyrosine kinase activation, genomic alterations, and drug sensitivity to osimertinib and savolitinib.
  • Assessed EGFR, MET, and ERBB3 signaling, dimerization, and interactions, including effects of exogenous MET overexpression.

Main Results:

  • HCC827OR cells showed MET amplification and sensitivity to the MET-TKI savolitinib.
  • ERBB3 phosphorylation correlated with TKI efficacy.
  • MET amplification led to decreased EGFR-ERBB3 interaction, increased MET-ERBB3 interaction, increased MET homodimers, and decreased EGFR homodimers, with exogenous MET overexpression partially mimicking this phenotype.

Conclusions:

  • MET amplification alters EGFR/MET/ERBB3 dimerization balance, shifting signaling dependence from EGFR to MET.
  • This provides crucial insights for developing novel therapeutic strategies against acquired resistance in EGFR-mutated NSCLC.
Keywords:
EGFR mutationMET amplificationdimerizationdrug resistancelung cancerosimertinib

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