Oncotarget

Research Papers:

Antitumor profile of the PI3K inhibitor ZSTK474 in human sarcoma cell lines

Nachi Namatame, Naomi Tamaki, Yuya Yoshizawa, Mutsumi Okamura, Yumiko Nishimura, Kanami Yamazaki, Miwa Tanaka, Takuro Nakamura, Kentaro Semba, Takao Yamori, Shin-ichi Yaguchi and Shingo Dan _

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Oncotarget. 2018; 9:35141-35161. https://doi.org/10.18632/oncotarget.26216

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Abstract

Nachi Namatame1,2, Naomi Tamaki1, Yuya Yoshizawa1, Mutsumi Okamura1, Yumiko Nishimura1, Kanami Yamazaki1, Miwa Tanaka3, Takuro Nakamura3, Kentaro Semba4, Takao Yamori1,5, Shin-ichi Yaguchi1,2 and Shingo Dan1

1Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan

2R&D Center, Zenyaku Kogyo Co. Ltd, Tokyo, Japan

3Division of Carcinogenesis, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan

4Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan

5Present 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.


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