Gene interactions and pathways from curated databases and text-mining
Proc Natl Acad Sci U S A 2006, PMID: 16908864

Oncogenic Kit signaling and therapeutic intervention in a mouse model of gastrointestinal stromal tumor.

Rossi, Ferdinand; Ehlers, Imke; Agosti, Valter; Socci, Nicholas D; Viale, Agnes; Sommer, Gunhild; Yozgat, Yasemin; Manova, Katia; Antonescu, Cristina R; Besmer, Peter

Kit receptor-activating mutations are critical in the pathogenesis of gastrointestinal stromal tumors (GIST). We investigated mechanisms of oncogenic Kit signaling and the consequences of therapeutic intervention in a mouse model of human GIST. Treatment of GIST mice with imatinib decreased cell proliferation and increased apoptosis in the tumor. Analysis of tumor tissue from imatinib-treated mice showed diminished phosphatidylinositol 3-kinase (PI3-kinase) and mammalian target of rapamycin (mTOR) signaling suggesting that oncogenic Kit signaling critically contributes to the translational response in GIST. Treatment with RAD001 (everolimus), an mTOR inhibitor, diminished the translational response and cell proliferation in tumor lesions, pointing to mTOR inhibition as a therapeutic approach for imatinib-resistant GIST. Analysis of RNA expression profiles in GIST lesions with and without imatinib treatment showed changes in expression of IFN-inducible genes and cell cycle regulators. These results convincingly show that KitV558Delta/+ mice represent a unique faithful mouse model of human familial GIST, and they demonstrate the utility of these mice for preclinical investigations and to elucidate oncogenic signaling mechanisms by using genetic approaches and targeted pharmacological intervention.

Diseases/Pathways annotated by Medline MESH: Disease Models, Animal, Gastrointestinal Stromal Tumors
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Text Mining Data

mTOR ⊣ RAD001: " Treatment with RAD001 ( everolimus ), an mTOR inhibitor , diminished the translational response and cell proliferation in tumor lesions, pointing to mTOR inhibition as a therapeutic approach for imatinib-resistant GIST "

Manually curated Databases

No curated data.