Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC.
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.
Turke
Alexa B
AB
Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA.
Zejnullahu
Kreshnik
K
Wu
Yi-Long
YL
Song
Youngchul
Y
Dias-Santagata
Dora
D
Lifshits
Eugene
E
Toschi
Luca
L
Rogers
Andrew
A
Mok
Tony
T
Sequist
Lecia
L
Lindeman
Neal I
NI
Murphy
Carly
C
Akhavanfard
Sara
S
Yeap
Beow Y
BY
Xiao
Yun
Y
Capelletti
Marzia
M
Iafrate
A John
AJ
Lee
Charles
C
Christensen
James G
JG
Engelman
Jeffrey A
JA
Jänne
Pasi A
PA
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005784:Gene Amplification; D015870:Gene Expression; D017228:Hepatocyte Growth Factor; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009154:Mutation; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met; D052999:Quinazolinones / Q000494:pharmacology; D017978:Receptors, Growth Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C066855:HGF protein, human; D011518:Proto-Oncogene Proteins; D052999:Quinazolinones; D017978:Receptors, Growth Factor; C525726:dacomitinib; D017228:Hepatocyte Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met