MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling.
The epidermal growth factor receptor (EGFR) kinase inhibitors gefitinib and erlotinib are effective treatments for lung cancers with EGFR activating mutations, but these tumors invariably develop drug resistance. Here, we describe a gefitinib-sensitive lung cancer cell line that developed resistance to gefitinib as a result of focal amplification of the MET proto-oncogene. inhibition of MET signaling in these cells restored their sensitivity to gefitinib. MET amplification was detected in 4 of 18 (22%) lung cancer specimens that had developed resistance to gefitinib or erlotinib. We find that amplification of MET causes gefitinib resistance by driving ERBB3 (HER3)-dependent activation of PI3K, a pathway thought to be specific to EGFR/ERBB family receptors. Thus, we propose that MET amplification may promote drug resistance in other ERBB-driven cancers as well.
Engelman
Jeffrey A
JA
Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.
Zejnullahu
Kreshnik
K
Mitsudomi
Tetsuya
T
Song
Youngchul
Y
Hyland
Courtney
C
Park
Joon Oh
JO
Lindeman
Neal
N
Gale
Christopher-Michael
CM
Zhao
Xiaojun
X
Christensen
James
J
Kosaka
Takayuki
T
Holmes
Alison J
AJ
Rogers
Andrew M
AM
Cappuzzo
Federico
F
Mok
Tony
T
Lee
Charles
C
Johnson
Bruce E
BE
Cantley
Lewis C
LC
Jänne
Pasi A
PA
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D016466:CHO Cells; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors; D000077156:Gefitinib; D005784:Gene Amplification; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013450:Sulfones / Q000494:pharmacology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000077156:Gefitinib; D007211:Indoles; D019869:Phosphatidylinositol 3-Kinases; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019859:Proto-Oncogene Proteins c-met; D011799:Quinazolines; D020893:Receptor, ErbB-3; D017978:Receptors, Growth Factor; D013450:Sulfones; C480541:5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one; C000715470:MAS1 protein, human; C491743:MET protein, human