Imatinib upregulates compensatory integrin signaling in a mouse model of gastrointestinal stromal tumor and is more effective when combined with dasatinib Journal Article

Authors: Rossi, F.; Yozgat, Y.; de Stanchina, E.; Veach, D.; Clarkson, B.; Manova, K.; Giancotti, F. G.; Antonescu, C. R.; Besmer, P.
Article 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. ©2010 AACR.
Keywords: immunohistochemistry; signal transduction; mitogen activated protein kinase; controlled study; drug efficacy; nonhuman; antineoplastic agents; reproducibility of results; mouse; animals; mice; gastrointestinal stromal tumor; imatinib; gastrointestinal stromal tumors; proto-oncogene proteins c-kit; antineoplastic combined chemotherapy protocols; neoplasm proteins; animal experiment; animal model; down-regulation; enzyme activation; dasatinib; protein tyrosine kinase; pyrimidines; phosphatidylinositol 3 kinase; carcinogenesis; extracellular matrix; enzyme phosphorylation; western blotting; immunoprecipitation; single drug dose; real time polymerase chain reaction; upregulation; piperazines; up-regulation; disease models, animal; src-family kinases; thiazoles; focal adhesion kinase; integrin; integrins; stat protein
Journal Title: Molecular Cancer Research
Volume: 8
Issue: 9
ISSN: 1541-7786
Publisher: American Association for Cancer Research  
Date Published: 2010-09-01
Start Page: 1271
End Page: 1283
Language: English
DOI: 10.1158/1541-7786.mcr-10-0065
PUBMED: 20736294
PROVIDER: scopus
PMCID: PMC2952175
Notes: --- - "Export Date: 20 April 2011" - "CODEN: MCROC" - "Source: Scopus"
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MSK Authors
  1. Darren Veach
    59 Veach
  2. Cristina R Antonescu
    596 Antonescu
  3. Ferdinando Rossi
    19 Rossi
  4. Peter Besmer
    76 Besmer
  5. Yasemin Yozgat
    4 Yozgat