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MET amplification increases the metastatic spread of EGFR-mutated NSCLC

Simon Baldacci1, Zoulika Kherrouche2, Vincent Cockenpot3

  • 1Thoracic Oncology Department, CHU Lille, Siric OncoLille, F-59000, Lille, France; Univ Lille, Lille, France; Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies, F-59000, Lille, France.

Lung Cancer (Amsterdam, Netherlands)
|November 16, 2018
PubMed
Abstract

Insights

MET amplification in EGFR-mutated non-small cell lung cancer (NSCLC) drives aggressive tumor growth and metastasis. Targeting MET can reverse this phenotype, suggesting new therapeutic strategies for resistant lung cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI) in metastatic EGFR-mutated non-small cell lung cancer (NSCLC) occurs in 5-20% of cases.
  • MET amplification is a known mechanism of acquired resistance to EGFR-TKI therapy.
  • The impact of MET amplification on tumor and patient phenotype is not well understood.

Purpose of the Study:

  • To investigate the in vitro and in vivo effects of MET amplification on the biological properties of EGFR-mutated NSCLC cells.
  • To evaluate the clinical significance of MET amplification in EGFR-mutated NSCLC patients progressing on EGFR-TKI therapy.

Main Methods:

  • In vitro studies using the HCC827 cell line (EGFR-mutated NSCLC) to assess the impact of MET amplification on proliferation, anchorage-independent growth, anoikis resistance, migration, and epithelial-to-mesenchymal transition.
  • In vivo studies to evaluate tumor growth and metastatic spread in a xenograft model.
  • Clinical analysis of EGFR-mutated NSCLC patients with MET amplification or high MET overexpression on re-biopsy after EGFR-TKI progression.

Main Results:

  • MET amplification significantly enhanced proliferation, anchorage-independent growth, anoikis resistance, migration, and induced epithelial-to-mesenchymal transition in vitro.
  • In vivo, MET amplification led to increased tumor growth and metastatic spread.
  • MET-TKI treatment reversed the aggressive phenotype induced by MET amplification.
  • Patients with MET amplification showed a shorter time to new metastases after EGFR-TKI progression compared to those with high MET overexpression without amplification.

Conclusions:

  • MET amplification promotes metastatic spread in EGFR-mutated NSCLC, even with an existing driver mutation.
  • These findings highlight the need for therapeutic strategies to prevent or target MET amplification in NSCLC.
  • Targeting MET signaling is a promising approach for overcoming acquired resistance to EGFR-TKI therapy.
Keywords:
EGFRMETMetastasisNon small cell lung cancerTyrosine kinase inhibitor

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