Preexistence and Clonal Selection of MET Amplification in EGFR Mutant NSCLC

Alexa B. Turke, Kreshnik Zejnullahu, Yi Long Wu, Youngchul Song, Dora Dias-Santagata, Eugene Lifshits, Luca Toschi, Andrew Rogers, Tony Mok, Lecia Sequist, Neal I. Lindeman, Carly Murphy, Sara Akhavanfard, Beow Y. Yeap, Yun Xiao, Marzia Capelletti, A. John Iafrate, Charles Lee, James G. Christensen, Jeffrey A. EngelmanPasi A. Jänne

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)77-88
Number of pages12
JournalCancer Cell
Volume17
Issue number1
DOIs
Publication statusPublished - Jan 19 2010

Keywords

  • CELLCYCLE

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

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  • Cite this

    Turke, A. B., Zejnullahu, K., Wu, Y. L., Song, Y., Dias-Santagata, D., Lifshits, E., Toschi, L., Rogers, A., Mok, T., Sequist, L., Lindeman, N. I., Murphy, C., Akhavanfard, S., Yeap, B. Y., Xiao, Y., Capelletti, M., Iafrate, A. J., Lee, C., Christensen, J. G., ... Jänne, P. A. (2010). Preexistence and Clonal Selection of MET Amplification in EGFR Mutant NSCLC. Cancer Cell, 17(1), 77-88. https://doi.org/10.1016/j.ccr.2009.11.022