Abstract
Abstract Gastrointestinal stromal tumors (GIST) is gastrointestinal tract sarcoma which commonly contains a mutation in the KIT or PDGFRA. Imatinib mesylate, a specific tyrosine kinase inhibitor of the KIT and PDGFRA, causes regression or stabilization of disease in most of the patients with metastatic GIST. However, acquired resistance to imatinib is inevitable. Recently, E26 variant 1 (ETV1) pathway was found to be a key downstream effector of KIT. In this study, we explored the role of ETVI and its downstream effectors pathway in GIST by bioinformatics analysis, and identified potential novel agents that target ETV1 pathway of GISTs by using expression profile and a pattern-matching software “Connectivity Map” (CMAP), and confirmed the efficacy of novel agents by using GIST cell line in vitro assay. By using CMAP, four drugs with potential ETV1-inhibition effect were identified: suberanilohydroxamic acid (SAHA,Vorinostat) and trichostatin, two histone deacetylase inhibitors (HDACI), and trifluoperazine (TFP) and thioridazine (TDZ), two drugs of phenothiazine class. All four drugs were found to have ETV1-down regulating effect by immunoblotting. Phenothiazine could induce apoptosis and autophagy in GIST. Treatment of phenothiazine was found paradoxically up-regulate MEK activity. Combination of MEK inhibitor and phenothiazine showed great synergistic effect in exerting cytotoxicity against GIST cell lines. Our study established phenothiazine as a new class of agent with therapeutic effect in GIST, and combination of phenothiazine and MEK inhibitor showed great potential in GIST treatment. Citation Format: Chueh-Chuan Yen, Li-Tzong Chen, Chien-Feng Li. Exploring novel treatment agent in GIST by using connectivity map. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3540.
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