Abstract 6993: Development of synthetic lethal compounds targeting RB1-SUCLA2 deletion in advanced prostate cancer

Abstract The deletion of the tumor suppressor gene RB1 frequently occurs upon metastatic and/or castration-resistant conversion in prostate cancer. This extensive chromosomal loss associated with RB1 deletion also results in the loss of additional neighboring genes. Inhibition of gene products that compensate for these defective deletions can induce tumor-specific synthetic lethality. Our previous research demonstrated that SUCLA2 is collaterally deleted with RB1 often in advanced prostate cancer and that 5-Isopropyl-2-methyl-1, 4-benzoquinone (TQ) selectively kills SUCLA2-deficient tumors. In this study, we explored the target of TQ and the mechanism of action. To determine the binding targets of TQ, we synthesized a biotinylated alkyl TQ enabling target identification via mass spectrometry analysis. Four mitochondrial enzymes were identified (W, X, Y, and Z). Enzymatic assays revealed that only enzyme X was inhibited by TQ in a dose-dependent manner. Enzyme X composes qn enzymatic complex consisting of six alpha and six beta subunits, which TQ dissociated. Notably, TQ irreversibly depleted 2-oxoglutarate and glycine in SUCLA2 knockout (KO) cells, while TQ did not affect these metabolites in SUCLA2-reconstituted cells. Adding cell-permeable 2-oxoglutarate prevented TQ-induced apoptosis in SUCLA2 KO cells, suggesting that TQ induces apoptosis by depleting tricarboxylic acid (TCA) cycle intermediates, likely through the inhibition of enzyme X. We are currently developing new TQ derivatives to improve IC50 and pharmacokinetics. This research opens avenues for novel therapeutic strategies targeting metabolic pathways through this distinctive mechanism. Citation Format: Susumu Kohno, Chiaki Takahashi. Development of synthetic lethal compounds targeting RB1-SUCLA2 deletion in advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6993.