Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC by Turke Alexa B, Zejnullahu Kreshnik, Wu Yi-Long, Song Youngchul, Dias-Santagata Dora, Lifshits Eugene, Toschi Luca, Rogers Andrew, Mok Tony, Sequist Lecia, Lindeman Neal I, Murphy Carly, Akhavanfard Sara, Yeap Beow Y, Xiao Yun, Capelletti Marzia, Iafrate A John, Lee Charles, Christensen James G, Engelman Jeffrey A, Jänne Pasi A in Cancer cell (2010). PubMed

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.

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