國家衛生研究院 NHRI:Item 3990099045/12076
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    题名: Identification of phenothiazine as an ETV1targeting agent in gastrointestinal stromal tumors using the Connectivity Map
    作者: Yen, CC;Chen, LT;Li, CF;Chen, SC;Chua, WY;Lin, YC;Yen, CH;Chen, YC;Yang, MH;Chao, Y;Fletcher, JA
    贡献者: National Institute of Cancer Research
    摘要: Gastrointestinal stromal tumors (GISTs) are gastrointestinal tract sarcomas that commonly contain a mutation in the tyrosine kinases, KIT and plateletderived growth factor receptor A (PDGFRA). Imatinib, sunitinib and regorafenib are all effective tyrosine kinase inhibitors; however, acquired resistance is inevitable. The E26 variant 1 (ETV1) pathway has been found to be a key downstream effector of KIT and is therefore a reasonable therapeutic target for this disease. In this study, we explored the potential agents targeting ETV1 in GISTs by uploading an ETV1 knockout gene signature of GIST cell lines to the patternmatching software 'Connectivity Map'. The activity and mechanisms of identified agents were examined using an in vitro model. Four drugs were identified: Suberanilohydroxamic acid and trichostatin [two histone deacetylase inhibitors (HDACIs)] and trifluoperazine and thioridazine (two phenothiazineclass drugs). Western blot analysis demonstrated that all four drugs had ETV1downregulating effects. As HDACIs have been previously studied in GISTs, we focused on phenothiazine. Phenothiazine was found to exert cytotoxicity and to induce apoptosis and autophagy in GISTs. Treatment with phenothiazine had little effect on the KIT/AKT/mammalian target of rapamycin (mTOR) pathway, but instead upregulated extracellularsignalregulated kinase (ERK) activity. A combination of phenothiazine and a MEK inhibitor had a synergistic cytotoxic effect on GISTs. Western blot analysis indicated that ELK1 and early growth response 1 (EGR1) were activated/upregulated following phenothiazine treatment, and the MEK inhibitor/phenothiazine combination downregulated the ERK/ELK1/EGR1 pathway, resulting in diminished autophagy, as well as enhanced apoptosis. On the whole, the findings of this study established phenothiazine as a novel class of therapeutic agents in GIST treatment and demonstrate that a combination of phenothiazine and MEK inhibitor has great potential for use in the treatment of GISTs.
    日期: 2019-06-21
    關聯: International Journal of Oncology. 2019 Jun 21;55(2):536-546.
    Link to: http://dx.doi.org/10.3892/ijo.2019.4829
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1019-6439&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000476987200016
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85068883961
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