MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling

Science. 2007 May 18;316(5827):1039-43. doi: 10.1126/science.1141478. Epub 2007 Apr 26.

Abstract

The epidermal growth factor receptor (EGFR) kinase inhibitors gefitinib and erlotinib are effective treatments for lung cancers with EGFR activating mutations, but these tumors invariably develop drug resistance. Here, we describe a gefitinib-sensitive lung cancer cell line that developed resistance to gefitinib as a result of focal amplification of the MET proto-oncogene. inhibition of MET signaling in these cells restored their sensitivity to gefitinib. MET amplification was detected in 4 of 18 (22%) lung cancer specimens that had developed resistance to gefitinib or erlotinib. We find that amplification of MET causes gefitinib resistance by driving ERBB3 (HER3)-dependent activation of PI3K, a pathway thought to be specific to EGFR/ERBB family receptors. Thus, we propose that MET amplification may promote drug resistance in other ERBB-driven cancers as well.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • CHO Cells
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cricetinae
  • Cricetulus
  • Drug Resistance, Neoplasm
  • Enzyme Inhibitors
  • Gefitinib
  • Gene Amplification*
  • Humans
  • Indoles / pharmacology
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-met
  • Quinazolines / pharmacology*
  • Quinazolines / therapeutic use
  • Receptor, ErbB-3 / metabolism*
  • Receptors, Growth Factor / genetics*
  • Receptors, Growth Factor / metabolism
  • Signal Transduction*
  • Sulfones / pharmacology

Substances

  • 5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Indoles
  • Proto-Oncogene Proteins
  • Quinazolines
  • Receptors, Growth Factor
  • Sulfones
  • Phosphatidylinositol 3-Kinases
  • MET protein, human
  • Proto-Oncogene Proteins c-met
  • Receptor, ErbB-3
  • Proto-Oncogene Proteins c-akt
  • Gefitinib