Abstract 1207: Thymoquinone-based drug development targeting SUCLA2 loss in advanced prostate cancer

RB1 gene is often homozygously deleted or mutated in prostate adenocarcinomas following acquirement of castration resistance and/or metastatic ability. We found that SUCLA2 gene is frequently involved in the deletion of the RB1 gene region in advanced prostate cancer. SUCLA2 constitutes the β-subunit of succinate CoA ligase heterodimer that reversibly converts succinyl CoA into succinate. We sought the possibility that deletion of SUCLA2 gives rise to a metabolic vulnerability that could be targeted therapeutically. Indeed, we found a significant metabolic shift in SUCLA2-deleted prostate cancer cells, including lower mitochondrialrespiratory activity. By screening a number of libraries for compounds that induce cell death selectively in SUCLA2-deficient prostate cancer cells, we identified thymoquinone (2-isopropyl-5-methylbenzo-1,4-quinone) and PMA (phorbol-12-myristate-13-acetate) from a natural compound library. Thymoquinone has been known for its anti-tumor efficacy. We examined the biological activity of a number of thymoquinone derivatives and synthesized chemical probes to identify molecular target of this agent. In this presentation, we will propose a new therapeutic approach to advanced prostate cancers. Citation Format: Chiaki Takahashi. Thymoquinone-based drug development targeting SUCLA2 loss in advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1207.