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• W2898036491 abstract "// Nachi Namatame 1, 2 , Naomi Tamaki 1 , Yuya Yoshizawa 1 , Mutsumi Okamura 1 , Yumiko Nishimura 1 , Kanami Yamazaki 1 , Miwa Tanaka 3 , Takuro Nakamura 3 , Kentaro Semba 4 , Takao Yamori 1, 5 , Shin-ichi Yaguchi 1, 2 and Shingo Dan 1 1 Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan 2 R&D Center, Zenyaku Kogyo Co. Ltd, Tokyo, Japan 3 Division of Carcinogenesis, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan 4 Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan 5 Present address: Center for Product Evaluation, Pharmaceuticals and Medical Devices Agency, Tokyo, Japan Correspondence to: Shingo Dan, email: sdan@jfcr.or.jp Keywords: sarcoma; PI3K; anticancer agent; cell line panel; oncogenic chromosomal translocation Received: April 10, 2018      Accepted: September 26, 2018      Published: October 12, 2018 ABSTRACT Treatment of patients with advanced sarcoma remains challenging due to lack of effective medicine, with the development of novel drugs being of keen interest. A pan-PI3K inhibitor, ZSTK474, has been evaluated in clinical trials against a range of advanced solid tumors, with clinical benefit shown in sarcoma patients. In the present study, we developed a panel of 14 human sarcoma cell lines and investigated the antitumor effect of 24 anticancer agents including ZSTK474, other PI3K inhibitors, and those clinically used for sarcoma treatment. ZSTK474 exhibited a similar antiproliferative profile to other PI3K inhibitors but was clearly different from the other drugs examined. Indeed, ZSTK474 inhibited PI3K-downstream pathways, in parallel to growth inhibition, in all cell lines examined, showing proof-of-concept of PI3K inhibition. In addition, ZSTK474 induced apoptosis selectively in Ewing’s sarcoma (RD-ES and A673), alveolar rhabdomyosarcoma (SJCRH30) and synovial sarcoma (SYO-1, Aska-SS and Yamato-SS) cell lines, all of which harbor chromosomal translocation and resulting oncogenic fusion genes, EWSR1-FLI1 , PAX3-FOXO1 and SS18-SSX , respectively. Finally, animal experiments confirmed the antitumor activity of ZSTK474 in vivo , with superior efficacy observed in translocation-positive cells. These results suggest that ZSTK474 could be a promising drug candidate for treating sarcomas, especially those harboring chromosomal translocation." @default.
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• W2898036491 date "2018-10-12" @default.
• W2898036491 modified "2023-10-15" @default.
• W2898036491 title "Antitumor profile of the PI3K inhibitor ZSTK474 in human sarcoma cell lines" @default.
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• W2898036491 doi "https://doi.org/10.18632/oncotarget.26216" @default.
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