title: Pharmacological Inhibition of KIT Activates MET Signaling in Gastrointestinal Stromal Tumors.
abstract: Gastrointestinal stromal tumors (GIST) are the most common adult sarcomas and the oncogenic driver is usually a KIT or PDGFRA mutation. Although GISTs are often initially sensitive to imatinib or other tyrosine kinase inhibitors, resistance generally develops, necessitating backup strategies for therapy. In this study, we determined that a subset of human GIST specimens that acquired imatinib resistance acquired expression of activated forms of the MET oncogene. MET activation also developed after imatinib therapy in a mouse model of GIST (KitV558del/+ mice), where it was associated with increased tumor hypoxia. MET activation also occurred in imatinib-sensitive human GIST cell lines after imatinib treatment in vitro. MET inhibition by crizotinib or RNA interference was cytotoxic to an imatinib-resistant human GIST cell population. Moreover, combining crizotinib and imatinib was more effective than imatinib alone in imatinib-sensitive GIST models. Finally, cabozantinib, a dual MET and KIT small-molecule inhibitor, was markedly more effective than imatinib in multiple preclinical models of imatinib-sensitive and imatinib-resistant GIST. Collectively, our findings showed that activation of compensatory MET signaling by KIT inhibition may contribute to tumor resistance. Furthermore, our work offered a preclinical proof of concept for MET inhibition by cabozantinib as an effective strategy for GIST treatment.
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Noah A
authors.initials: NA
authors.lastname: Cohen
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Shan
authors.initials: S
authors.lastname: Zeng
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Seifert
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Teresa S
authors.initials: TS
authors.lastname: Kim
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Sorenson
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Greer
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Beckman
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Santamaria-Barria
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Megan H
authors.initials: MH
authors.lastname: Crawley
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Green
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Rossi
authors.affiliation: Department of Developmental Biology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Peter
authors.initials: P
authors.lastname: Besmer
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. dematter@mskcc.org.
authors.forename: Ronald P
authors.initials: RP
authors.lastname: DeMatteo
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010879:Piperazines / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors* / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D015398:Signal Transduction; D000077210:Sunitinib; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D001549:Benzamides; D007211:Indoles; D010879:Piperazines; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; C558660:cabozantinib; D000068877:Imatinib Mesylate; C491743:MET protein, human; D019009:Proto-Oncogene Proteins c-kit; D019859:Proto-Oncogene Proteins c-met; D000077210:Sunitinib
references.citation: J Clin Oncol. 2008 Feb 1;26(4):620-5
references.pmid: 18235121
references.citation: Cancer Res. 2008 Mar 1;68(5):1471-7
references.pmid: 18316611
references.citation: Genes Chromosomes Cancer. 2008 Dec;47(12):1025-37
references.pmid: 18709663
references.citation: Nature. 2010 Dec 16;468(7326):968-72
references.pmid: 21107320
references.citation: PLoS One. 2011;6(8):e20294
references.pmid: 21826194
references.citation: Am J Surg Pathol. 2011 Nov;35(11):1712-21
references.pmid: 21997692
references.citation: Mol Cancer Ther. 2011 Dec;10(12):2298-308
references.pmid: 21926191
references.citation: Annu Rev Med. 2012;63:247-58
references.pmid: 22017446
references.citation: Nat Rev Cancer. 2012 Feb;12(2):89-103
references.pmid: 22270953
references.citation: Lancet. 2013 Jan 26;381(9863):295-302
references.pmid: 23177515
references.citation: Cancer Discov. 2013 Jun;3(6):658-73
references.pmid: 23729478
references.citation: Clin Lung Cancer. 2013 Sep;14(5):473-80
references.pmid: 23790969
references.citation: Int J Cancer. 2013 Dec 1;133(11):2737-43
references.pmid: 23716303
references.citation: J Clin Oncol. 2013 Oct 10;31(29):3639-46
references.pmid: 24002501
references.citation: Nat Med. 2013 Nov;19(11):1389-400
references.pmid: 24202392
references.citation: Clin Cancer Res. 2014 May 1;20(9):2350-62
references.pmid: 24583793
references.citation: Ann Surg. 2000 Jan;231(1):51-8
references.pmid: 10636102
references.citation: Blood. 2000 Aug 1;96(3):925-32
references.pmid: 10910906
references.citation: FASEB J. 2001 Mar;15(3):645-58
references.pmid: 11259383
references.citation: Oncogene. 2001 Aug 16;20(36):5054-8
references.pmid: 11526490
references.citation: Lab Invest. 2002 May;82(5):663-5
references.pmid: 12004007
references.citation: Hum Pathol. 2002 May;33(5):466-77
references.pmid: 12094371
references.citation: N Engl J Med. 2002 Aug 15;347(7):472-80
references.pmid: 12181401
references.citation: Science. 2003 Jan 31;299(5607):708-10
references.pmid: 12522257
references.citation: Cancer Cell. 2003 Apr;3(4):347-61
references.pmid: 12726861
references.citation: Proc Natl Acad Sci U S A. 2003 May 27;100(11):6706-11
references.pmid: 12754375
references.citation: Nat Rev Mol Cell Biol. 2003 Dec;4(12):915-25
references.pmid: 14685170
references.citation: Hepatology. 2004 Feb;39(2):422-32
references.pmid: 14767995
references.citation: Lancet. 2004 Sep 25-Oct 1;364(9440):1127-34
references.pmid: 15451219
references.citation: Br J Cancer. 1995 Oct;72(4):889-95
references.pmid: 7547236
references.citation: Nature. 1996 Nov 14;384(6605):173-6
references.pmid: 8906793
references.citation: Science. 1998 Jan 23;279(5350):577-80
references.pmid: 9438854
references.citation: Gastroenterology. 2005 Feb;128(2):270-9
references.pmid: 15685537
references.citation: Cancer Lett. 2005 Jul 8;225(1):1-26
references.pmid: 15922853
references.citation: Clin Cancer Res. 2005 Jun 1;11(11):4182-90
references.pmid: 15930355
references.citation: Lancet. 2006 Oct 14;368(9544):1329-38
references.pmid: 17046465
references.citation: Semin Diagn Pathol. 2006 May;23(2):70-83
references.pmid: 17193820
references.citation: Mod Pathol. 2007 May;20(5):529-37
references.pmid: 17334345
references.citation: Cancer Res. 2007 May 1;67(9):4408-17
references.pmid: 17483355
references.citation: Science. 2007 May 18;316(5827):1039-43
references.pmid: 17463250
references.citation: Oncogene. 2007 Jun 7;26(27):3909-19
references.pmid: 17325667