Reference Detail

Ref Type

Journal Article

PMID

(19139124)

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	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	8	1	2009 Jan	152-9	Mol Cancer Ther

URL

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.

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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_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
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