Abstract 455: Targeting CARM1- expressing ovarian cancers with HSP-70 inhibitors

Abstract Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer-related deaths in the United States, characterized by its genetic heterogeneity and the urgent need to develop novel therapeutic strategies in a personalized manner. Coactivator-associated arginine methyltransferase 1 (CARM1) is an enzyme responsible for post-translational modifications of protein substrates on arginine residues. CARM1 is often overexpressed and functions as an oncogene in several cancer types. Notably, high-grade serous ovarian carcinoma (HGSOC) exhibits the highest rates of CARM1 amplification, with approximately 20% of cases showing overexpression, which correlates with poor survival outcomes in EOC patients. This study aimed to identify potential therapeutic targets for EOC cells with CARM1 amplification. We conducted an unbiased evaluation of a custom set of 27 small-molecule inhibitors to identify agents selectively effective against CARM1-expressing EOC cells, leading to the identification of the HSP-70 inhibitor AP-4-139B as the most potent candidate. HSP-70 is a crucial part of the protein folding machinery, and its levels are upregulated in multiple types of cancer and serve as a substrate for CARM1 enzymatic activity; however, the implications of HSP-70 modification by CARM1 remain unclear. The CRISPR-Cas9-based knockout technology was employed to analyze the effect of CARM1 knockout on cell proliferation in EOC cells, which demonstrated that CARM1 knockout significantly slowed cell growth in EOC cells. Synthetic lethality of CARM1-expressing cells upon HSP-70 inhibition by AP-4-139B was validated in both the ovarian cancer cell model system and the xenograft model. Mechanistically, AP-4-139B treatment induced apoptotic cell death in CARM1-high EOC cells through activation of the apoptotic pathway as analyzed by cell proliferation assay, apoptotic assay, and immunoblotting of apoptotic markers. Our findings indicate that CARM1-high cells are selectively sensitive to HSP-70 inhibitors as a single agent. HSP-70 inhibition alone will be sufficient to induce apoptosis and inhibit tumor growth in a CARM1-dependent manner ex vivo and in vivo. Thus, these findings will have far-reaching implications for developing personalized therapeutic strategies based on CARM1 amplification. The therapeutic and mechanistic rationale for targeted therapy on patients with CARM1 high EOC who are most likely to benefit from HSP-70 inhibitor treatment. Citation Format: Sangeeta Kumari, Shraddha Gupta, Aisha Jamil, Sergey Karakashev. Targeting CARM1- expressing ovarian cancers with HSP-70 inhibitors [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 455.