title: Imatinib upregulates compensatory integrin signaling in a mouse model of gastrointestinal stromal tumor and is more effective when combined with dasatinib.
abstract: Activating mutations in the Kit receptor tyrosine kinase are associated with gastrointestinal stromal tumor (GIST). Imatinib inhibits Kit and is front-line therapy for GIST. However, imatinib most often elicits a partial response or stable disease, and most GIST patients who initially respond to imatinib eventually acquire resistance. Thus, improved treatment strategies for GIST are needed. We investigated the role of Src family kinases (SFK) in tumorigenesis in a mouse model of human GIST. The SFKs Src and Lyn were active in GIST, and surprisingly, imatinib treatment stimulated their phosphorylation/activation. We show that integrin signaling activates focal adhesion kinase and, consequently, SFKs in GIST and that imatinib enhances integrin signaling, implying a role for the extracellular matrix and integrin signaling in tumor maintenance and imatinib resistance. Dasatinib, an inhibitor of SFKs and Kit, inhibited SFK and focal adhesion kinase activation in GIST but also inhibited Kit and Kit-dependent downstream signaling pathways including phosphoinositide 3-kinase and mitogen-activated protein kinase, but not signal transducer and activator of transcription (STAT) signaling. Whereas dasatinib and imatinib alone both produced a minimal histopathologic response, combination therapy improved their efficacy, leading to increased necrosis in GIST. These results highlight the importance of SFK and STAT signaling in GIST and suggest that the clinical efficacy of imatinib may be limited by the stimulation of integrin signaling.
authors.affiliation: Developmental Biology Program, Sloan-Kettering Institute, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Rossi
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Yozgat
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.forename: Darren
authors.initials: D
authors.lastname: Veach
authors.forename: Bayard
authors.initials: B
authors.lastname: Clarkson
authors.forename: Katia
authors.initials: K
authors.lastname: Manova
authors.forename: Filippo G
authors.initials: FG
authors.lastname: Giancotti
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
authors.forename: Peter
authors.initials: P
authors.lastname: Besmer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides; D000069439:Dasatinib; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D016023:Integrins / Q000378:metabolism*; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D016023:Integrins; D009363:Neoplasm Proteins; D010879:Piperazines; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D019061:src-Family Kinases; D000069439:Dasatinib