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|Ref Type||Journal Article|
|Authors||Huynh H, Lee JW, Chow PK, Ngo VC, Lew GB, Lam IW, Ong HS, Chung A, Soo KC|
|Title||Sorafenib induces growth suppression in mouse models of gastrointestinal stromal tumor.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. Current therapeutic options include surgery and targeted molecular approaches such as imatinib and sunitinib. Our aim was to establish patient-derived GIST xenografts for the use of screening new drugs and improving current treatment regimens used in GIST. In this present study, we investigate the antitumor activity of sorafenib against patient-derived GIST xenografts. Murine xenograft models were given two oral doses of sorafenib daily for 30 days and growth of established tumor xenografts was monitored at least twice weekly by vernier caliper measurements. Western blotting was then used to determine changes in proteins in these xenografts before and after sorafenib therapy. Apoptotic and cell proliferation were analyzed by immunohistochemisty. Our data found that oral administration of sorafenib to mice, bearing patient-derived GIST xenografts, resulted in dose-dependent inhibition of tumor growth. Sorafenib-induced growth inhibition was associated with decreased cell proliferation, increased apoptosis, and reduction in tumor angiogenesis. Western blot analysis revealed that sorafenib inhibited C-Raf, phospho-extracellular signal-regulated kinase 1/2, and phospho-MEK1 (Thr286) slightly as well as phospho-c-Kit (Tyr568/Tyr570), phospho- platelet-derived growth factor receptor beta (Tyr1021), and phospho-Flk1 (Tyr951), suggesting that sorafenib inhibited GIST growth by blocking the Raf/MEK/extracellular signal-regulated kinase pathway and angiogenesis. Sorafenib also induced cell cycle arrest, evident through increased levels of p15 and p27 and decreased levels of p21, cyclin A, cyclin B1, and cdc-2. Our study provides a strong rationale for the clinical investigation of sorafenib in patients with GIST as well as an established platform for further drug evaluation studies using GIST xenograft models.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|KIT P551_V555delinsTL||gastrointestinal stromal tumor||sensitive||Sorafenib||Preclinical - Pdx||Actionable||In a preclinical study, Nexavar (sorafenib) inhibited Erk signaling, induced apoptosis, resulted in tumor growth inhibition in patient derived xenograft models of gastrointestinal stromal tumor harboring KIT P551_V555delinsTL (PMID: 19139124).||19139124|
|KIT P551_V555del||gastrointestinal stromal tumor||sensitive||Sorafenib||Preclinical - Pdx||Actionable||In a preclinical study, Nexavar (sorafenib) inhibited Erk signaling, induced apoptosis, resulted in tumor growth inhibition in patient derived xenograft models of gastrointestinal stromal tumor harboring KIT P551_V555del (PMID: 19139124).||19139124|