Abstract 223: Evaluating the therapeutic potential of MDM2 inhibitor RG-7388 and epigenetic modulator CM-272 in cisplatin-resistant ovarian cancer

Abstract Ovarian cancer (OC) is the deadliest gynecological malignancy, often presenting late diagnosis and exhibiting treatment resistance, partly due to dysregulation of the crucial tumor suppressor p53. The oncoprotein MDM2 also negatively regulates p53, and therefore, MDM2 specific inhibitors may offer potential therapeutic avenues through reactivation of p53 and reversing adverse epigenetic modifications causing growth or resistance. In this study, we investigated the therapeutic potential of the MDM2 inhibitor RG-7388, chemotherapeutic agent cisplatin, and the epigenetic modulator CM-272 in cisplatin-resistant A2780cis ovarian cancer cells. We first characterized the growth kinetics of cisplatin sensitive and resistant A2780 cell lines, which confirmed significantly longer doubling times in the resistant cells (approximately 35 hours versus 20 hours in sensitive cells). Treatment efficacy was evaluated through cell viability and cell death assays, along with the expression levels of DNMT1 and EZH2, which are key epigenetic regulators. Treatment of A2780cis cells with RG-7388 demonstrated significant anti-cancer activity, by reducing live cell populations by 42-48% through increased cell death. Despite resistance, qRT-PCR analysis revealed that both cisplatin and CM-272 treatments significantly suppressed DNMT1 expression by 96%A2780cis cells. Western blot analysis also confirmed that both RG-7388 and cisplatin reduced DNMT1 protein levels in A2780cis cells along with the most pronounced reduction of DNMT1 after CM-272 treatment. Notably, CM-272 significantly decreased the levels of EZH2 also while RG-7388 did not impact the EZH2 protein levels. Interestingly, treatments with RG-7388 and CM-272 drug combinations showed varied effects, while maintaining strong inhibition of PARP. Overall, our findings suggest that the MDM2 inhibitor RG-7388 could be a promising therapeutic agent for cisplatin-resistant ovarian cancer, particularly because of its ability to modulateepigenetic regulators like DNMT1. However, the complex interplay between cell survival and epigenetic regulation in drug resistant cells warrant further investigation to optimize the outcomes of combination treatment strategies. Acknowledgement: This project was supported by the Royal Dames of Cancer Research Inc. Ft. Lauderdale, Florida Citation Format: Fatimah Alssamani, Umamaheswari Natarajan, Shyam Jaganathan, Appu Rathinavelu. Evaluating the therapeutic potential of MDM2 inhibitor RG-7388 and epigenetic modulator CM-272 in cisplatin-resistant ovarian 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 223.