Preexistence and Clonal Selection of MET Amplification in EGFR Mutant NSCLC

Cancer Cell. 2010 Jan 19;17(1):77-88. doi: 10.1016/j.ccr.2009.11.022.

Abstract

MET amplification activates ERBB3/PI3K/AKT signaling in EGFR mutant lung cancers and causes resistance to EGFR kinase inhibitors. We demonstrate that MET activation by its ligand, HGF, also induces drug resistance, but through GAB1 signaling. Using high-throughput FISH analyses in both cell lines and in patients with lung cancer, we identify subpopulations of cells with MET amplification prior to drug exposure. Surprisingly, HGF accelerates the development of MET amplification both in vitro and in vivo. EGFR kinase inhibitor resistance, due to either MET amplification or autocrine HGF production, was cured in vivo by combined EGFR and MET inhibition. These findings highlight the potential to prospectively identify treatment naive, patients with EGFR-mutant lung cancer who will benefit from initial combination therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics*
  • ErbB Receptors / genetics*
  • ErbB Receptors / metabolism
  • Gene Amplification
  • Gene Expression
  • Hepatocyte Growth Factor
  • Humans
  • In Situ Hybridization, Fluorescence
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Mice
  • Mutation
  • Polymerase Chain Reaction
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-met
  • Quinazolinones / pharmacology
  • Receptors, Growth Factor / genetics*
  • Receptors, Growth Factor / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • HGF protein, human
  • Proto-Oncogene Proteins
  • Quinazolinones
  • Receptors, Growth Factor
  • dacomitinib
  • Hepatocyte Growth Factor
  • EGFR protein, human
  • ErbB Receptors
  • MET protein, human
  • Proto-Oncogene Proteins c-met

Associated data

  • GEO/GSE18797