Author/Authors :
Turke، نويسنده , , Alexa B. and Zejnullahu، نويسنده , , Kreshnik and Wu، نويسنده , , Yi-Long and Song، نويسنده , , Youngchul and Dias-Santagata، نويسنده , , Dora and Lifshits، نويسنده , , Eugene and Toschi، نويسنده , , Luca and Rogers، نويسنده , , Andrew and Mok، نويسنده , , Tony and Sequist، نويسنده , , Lecia and Lindeman، نويسنده , , Neal I. and Murphy، نويسنده , , Carly and Akhavanfard، نويسنده , , Sara and Yeap، نويسنده , , Beow Y. and Xiao، نويسنده , , Yun and Capelletti، نويسنده , , Marzia and Iafrate، نويسنده , , A. John and Lee، نويسنده , , Charles and Christensen، نويسنده , , James G. and Engelman، نويسنده , , Jeffrey A. and Jنnne، نويسنده , , Pasi A.، نويسنده ,
Abstract :
Summary
plification 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.
