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Imatinib upregulates compensatory integrin signaling in a mouse model of gastrointestinal stromal tumor and is more effective when combined with dasatinib
- Publication Year :
- 2010
-
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. Mol Cancer Res; 8(9); 1271–83. ©2010 AACR.
- Subjects :
- Cancer Research
Integrins
Gastrointestinal Stromal Tumors
Dasatinib
Down-Regulation
Antineoplastic Agents
Biology
Receptor tyrosine kinase
Article
Piperazines
Mice
LYN
hemic and lymphatic diseases
Antineoplastic Combined Chemotherapy Protocols
medicine
Animals
Humans
Molecular Biology
neoplasms
GiST
Reproducibility of Results
Imatinib
digestive system diseases
Neoplasm Proteins
Up-Regulation
Disease Models, Animal
Proto-Oncogene Proteins c-kit
Thiazoles
Imatinib mesylate
Pyrimidines
src-Family Kinases
Oncology
Benzamides
Cancer research
biology.protein
Imatinib Mesylate
Signal transduction
Proto-oncogene tyrosine-protein kinase Src
medicine.drug
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....7ad29f58d03bc237a1f6666b94c8ca54