title: MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling.
abstract: 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.
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
authors.forename: Kreshnik
authors.initials: K
authors.lastname: Zejnullahu
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mitsudomi
authors.forename: Youngchul
authors.initials: Y
authors.lastname: Song
authors.forename: Courtney
authors.initials: C
authors.lastname: Hyland
authors.forename: Joon Oh
authors.initials: JO
authors.lastname: Park
authors.forename: Neal
authors.initials: N
authors.lastname: Lindeman
authors.forename: Christopher-Michael
authors.initials: CM
authors.lastname: Gale
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Zhao
authors.forename: James
authors.initials: J
authors.lastname: Christensen
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kosaka
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Holmes
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Rogers
authors.forename: Federico
authors.initials: F
authors.lastname: Cappuzzo
authors.forename: Tony
authors.initials: T
authors.lastname: Mok
authors.forename: Charles
authors.initials: C
authors.lastname: Lee
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Johnson
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
mesh_terms: 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
chemical_list: 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