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.
Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA.
Alexa B
AB
Turke
Kreshnik
K
Zejnullahu
Yi-Long
YL
Wu
Youngchul
Y
Song
Dora
D
Dias-Santagata
Eugene
E
Lifshits
Luca
L
Toschi
Andrew
A
Rogers
Tony
T
Mok
Lecia
L
Sequist
Neal I
NI
Lindeman
Carly
C
Murphy
Sara
S
Akhavanfard
Beow Y
BY
Yeap
Yun
Y
Xiao
Marzia
M
Capelletti
A John
AJ
Iafrate
Charles
C
Lee
James G
JG
Christensen
Jeffrey A
JA
Engelman
Pasi A
PA
Jänne
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