Abstract 3909: Potential antitumor effect of a pan-PI3K inhibitor ZSTK474 on human sarcoma cell lines

Abstract

Abstract Phosphatidylinositol-3 kinase (PI3K) is a key signaling molecule for tumor growth and survival, thus the PI3K pathway has been thought to be a promising target for cancer therapy. We previously identified a novel phosphatidylinositol-3 kinase (PI3K) inhibitor, ZSTK474, by its similarity of antiproliferative profile across the JFCR39 cancer cell line panel to a known PI3K inhibitor, LY294002. Since then, ZSTK474 has been evaluated in preclinical models as well as in clinical trials in the US and Japan against a range of advanced solid tumors. The US trial revealed that three of four sarcoma patients exhibited stable disease, suggesting possible clinical benefit in this disease. Treatment of patients with advanced sarcoma remains challenging due to lack of effective medicine. Therefore the results of clinical trial prompted us to examine antitumor activity of this compound in various subtypes of sarcomas. To this end, we developed a sarcoma panel comprising of 17 human sarcoma cell lines from a variety of subtypes and investigated the effect of ZSTK474 across the panel and compare it with those of other molecularly targeted agents and clinically used chemotherapeutic agents for the treatment of sarcoma, such as doxorubicin, paclitaxel and gemcitabine. As a result, ZSTK474 exhibited a unique antiproliferative profile that was similar to other PI3K inhibitor but clearly different from conventional chemotherapeutic drugs examined, as we previously reported using JFCR39 carcinoma cell line panel. Indeed, ZSTK474 inhibited PI3K-downstream pathways, in parallel to growth inhibition, in all the sarcoma cell lines examined, showing proof-of-concept of PI3K inhibition. Of note, ZSTK474 exerted a potent antiproliferative effect on SW684, a fibrosarcoma cell line and MES-SA/Dx5, and a uterine sarcoma cell line that acquired resistance to doxorubicin via overexpression of P-glycoprotein, while both exhibited resistance to most of the chemotherapeutic agents examined. Moreover, ZSTK474 induced extensive apoptosis selectively in Ewing’s sarcoma and alveolar rhabdomyosarcoma cell lines, both of which harbor chromosomal translocations and resulting fusion genes, EWSR1-FLI1 and PAX3-FOXO1, respectively, whereas remaining sarcoma cell lines as well as carcinoma cell lines examined so far hardly underwent apoptosis. Additional cell lines from synovial sarcoma harboring SS18-SSX1/2 fusion gene also underwent apoptosis, suggesting preferential induction of apoptosis in oncogenic chromosomal translocation positive sarcoma cells. Finally, animal experiments using nude mice bearing human sarcoma xenograft 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 sarcomas, especially those harboring oncogenic chromosomal translocation. Citation Format: Shingo Dan, Naomi Tamaki, Nachi Namatame, Yuya Yoshizawa, Mutsumi Okamura, Yumiko Nishimura, Kanami Yamazaki, Shin-ichi Yaguchi. Potential antitumor effect of a pan-PI3K inhibitor ZSTK474 on human sarcoma cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3909.