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

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.

SUBMITTER: Namatame N

PROVIDER: S-EPMC6205545 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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

Namatame Nachi N Tamaki Naomi N Yoshizawa Yuya Y Okamura Mutsumi M Nishimura Yumiko Y Yamazaki Kanami K Tanaka Miwa M Nakamura Takuro T Semba Kentaro K Yamori Takao T Yaguchi Shin-Ichi SI Dan Shingo S

Oncotarget 20181012 80

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 ...[more]

PMID: 30416685

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Project description:Translocation-related sarcomas (TRSs) harbor an oncogenic fusion gene generated by chromosome translocation and account for approximately one-third of all sarcomas; however, effective targeted therapies have not yet been established. We previously reported that a pan-PI3K inhibitor, ZSTK474, was suggested to be effective for sarcomas in a phase I clinical trial, and demonstrated its efficacy in preclinical model, particularly in cell lines from synovial sarcomas (SS), Ewing’s sarcomas (ES) and alveolar rhabdomyosarcomas (ARMS), all of which harbor chromosomal translocation. Actually, ZSTK474 selectively induced apoptosis in these types of sarcoma cell lines, but the precise mechanism of apoptosis induction remained unclear. Here, we performed transcriptional analyses in SS cell lines including Aska-SS, SYO-1, Yamato-SS and Fuji treated with or without ZSTK474. Gene set enrichment analyses (GSEA) and Gene ontology (GO) analysis revealed that SS cell lines treated with ZSTK474 significantly reduced signatures of PI3K signaling. In addition, upon treatment with ZSTK474, the expression of apoptosis and cell cycle related genes was significantly changed. Importantly, PI3K inhibitors triggered induction of PUMA and BIM, resulting in loss of mitochondrial membrane potential, and the expression knockdown of these genes by RNA interference efficiently suppressed the apoptosis, suggesting their functional involvement in the apoptosis progression. In contrast, TRS-derived cell lines/patient-derived cells from alveolar soft part sarcoma (ASPS), CIC-DUX4 sarcoma and dermatofibrosarcoma protuberans failed to undergo apoptosis nor induce PUMA and BIM expression, as well as cell lines derived from non-TRSs and carcinomas. These results indicate that PI3K inhibitors selectively induce apoptosis in selective TRSs such as ES and SS via the induction of PUMA and BIM and subsequent loss of mitochondrial membrane potential, which would be a proof of concept for PI3K-targeted therapy especially for such TRS patients.

Dataset Information

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

Publications

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

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