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 Senba, Takao Yamori, Shin Ichi Yaguchi, Shingo Dan

    Research output: Contribution to journalArticle

    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.

    Original languageEnglish
    Pages (from-to)35141-35161
    Number of pages21
    JournalOncotarget
    Volume9
    Issue number80
    Publication statusPublished - 2018 Oct 1

    Fingerprint

    Phosphatidylinositol 3-Kinases
    Sarcoma
    Cell Line
    Genetic Translocation
    Alveolar Rhabdomyosarcoma
    Pharmaceutical Preparations
    Synovial Sarcoma
    Ewing's Sarcoma
    Gene Fusion
    ZSTK474
    Antineoplastic Agents
    Medicine
    Clinical Trials
    Apoptosis
    Therapeutics
    Growth
    Neoplasms

    Keywords

    • Anticancer agent
    • Cell line panel
    • Oncogenic chromosomal translocation
    • PI3K
    • Sarcoma

    ASJC Scopus subject areas

    • Oncology

    Cite this

    Namatame, N., Tamaki, N., Yoshizawa, Y., Okamura, M., Nishimura, Y., Yamazaki, K., ... Dan, S. (2018). Antitumor profile of the PI3K inhibitor ZSTK474 in human sarcoma cell lines. Oncotarget, 9(80), 35141-35161.

    Antitumor profile of the PI3K inhibitor ZSTK474 in human sarcoma cell lines. / Namatame, Nachi; Tamaki, Naomi; Yoshizawa, Yuya; Okamura, Mutsumi; Nishimura, Yumiko; Yamazaki, Kanami; Tanaka, Miwa; Nakamura, Takuro; Senba, Kentaro; Yamori, Takao; Yaguchi, Shin Ichi; Dan, Shingo.

    In: Oncotarget, Vol. 9, No. 80, 01.10.2018, p. 35141-35161.

    Research output: Contribution to journalArticle

    Namatame, N, Tamaki, N, Yoshizawa, Y, Okamura, M, Nishimura, Y, Yamazaki, K, Tanaka, M, Nakamura, T, Senba, K, Yamori, T, Yaguchi, SI & Dan, S 2018, 'Antitumor profile of the PI3K inhibitor ZSTK474 in human sarcoma cell lines' Oncotarget, vol. 9, no. 80, pp. 35141-35161.
    Namatame N, Tamaki N, Yoshizawa Y, Okamura M, Nishimura Y, Yamazaki K et al. Antitumor profile of the PI3K inhibitor ZSTK474 in human sarcoma cell lines. Oncotarget. 2018 Oct 1;9(80):35141-35161.
    Namatame, Nachi ; Tamaki, Naomi ; Yoshizawa, Yuya ; Okamura, Mutsumi ; Nishimura, Yumiko ; Yamazaki, Kanami ; Tanaka, Miwa ; Nakamura, Takuro ; Senba, Kentaro ; Yamori, Takao ; Yaguchi, Shin Ichi ; Dan, Shingo. / Antitumor profile of the PI3K inhibitor ZSTK474 in human sarcoma cell lines. In: Oncotarget. 2018 ; Vol. 9, No. 80. pp. 35141-35161.
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