Abstract 3090: miRNA-221-5p-mediated epigenetic regulation promotes chemoresistance and offers therapeutic potential in ovarian cancer

Abstract Epithelial ovarian cancer (EOC) is a highly aggressive malignancy and the leading cause of gynecological cancer-related deaths. The majority of patients are diagnosed at advanced stages (III-IV), where treatment involves surgical debulking followed by platinum-based chemotherapy. While initial responses to therapy are often favorable, over 70% of advanced-stage EOC patients experience recurrence, typically accompanied by resistance to standard of care treatments. This chemoresistance significantly limits therapeutic success and worsens patient prognosis. Understanding the molecular mechanisms driving resistance is critical for developing effective therapeutic strategies. Emerging evidence highlights the role of miRNAs in regulating gene expression networks associated with DNA damage repair and chemoresistance. miRNA-221-5p has been implicated in modulating tumor progression and therapeutic responses in various cancers. Here, we investigate its role in ovarian cancer, focusing on regulating RAD18 and RAD51—key mediators of DNA damage tolerance and homologous recombination repair (HRR). Our analysis of miRNA expression in a panel of human ovarian cancer cell lines revealed low to undetectable levels of miRNA-221-5p, coupled with elevated expression of DNA damage response and repair genes such as RAD18 and RAD51. Our experimental data demonstrate that miRNA-221-5p regulates RAD18 and RAD51 transcripts through 3’-UTR, leading to their post-transcriptional repression and subsequent restoration of ovarian cancer cell sensitivity to platinum drugs. Mechanistically, our results confirm that miRNA-221-5p epigenetically regulates RAD18- and RAD51-mediated DNA damage tolerance and homologous recombination repair. Importantly, restoring miRNA-221-5p downregulates RAD18 and RAD51 and sensitizes chemoresistant ovarian cancer cells to platinum drugs, offering a promising strategy to enhance therapeutic outcomes. Overall, our data demonstrate that miRNA-221-5p is a critical regulator of chemotherapy-induced epigenetic and transcriptional alterations, making it a prospective therapeutic target for overcoming chemoresistance and avoiding EOC recurrence. Citation Format: Tasmin Rahman Omy, Naresh Sah, Mark Reedy, Ganesh Acharya, Komaraiah Palle. miRNA-221-5p-mediated epigenetic regulation promotes chemoresistance and offers therapeutic potential in 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 3090.