Abstract 6106: Epigenetic-miRNA regulatory circuit confers ovarian cancer chemoresistance through RAD18-mediated DNA damage tolerance and repair signaling

Abstract

Abstract Epithelial ovarian cancer (EOC) is the deadliest gynecological malignancy. This cancer typically is not detected, 70-80% of patients, until an advanced stage (stage III-IV). The standard of care OC entails complete surgical resection of all visible abdominal-pelvic tumors, followed by platinum-based chemotherapy combined with a taxane. New recommendations for patients responding to adjuvant therapy is to include a PARP inhibitor with or without bevacizumab for maintenance therapy. Despite initial responses, the majority of stage 3 & 4 more than 70% of OC patients experience recurrent disease. Frequently, individuals become resistant to these treatments. This dreadful circumstance highlights the pressing need to identify the molecular mechanisms underlying the disease's aggressive nature upon recurrence and the development of treatment resistance. Several genetic and epigenetic factors have been linked to the reprogramming of tumor cells by controlling the pattern of transcriptional and post-transcriptional gene expression. Particularly, the miRNA-mediated regulatory circuit plays a significant role in tumor progression and therapeutic responses. Our analysis of miRNA expression signature in human ovarian cancer cell line panel showed little to no expression of miR221_5p and a corresponding increase in DNA damage response and repair gene RAD18 expression. RAD18 plays a critical role in cellular DNA damage tolerance and repair activity against chemotherapeutics, including platinum drugs. Similarly, loss of miRNA221_5p is associated with aggressive tumor cell growth, stemness, chemoresistance to platinum drugs, and poor prognosis in several cancers. Based on this information, we have hypothesized that miR221_5p regulates RAD18-mediated DNA damage tolerance and repair and may offer novel therapeutic intervention to overcome EOC chemoresistance. Our experimental data confers that miR221_5p post-transcriptionally regulates RAD18 by binding to its 3’-UTR region and restores OC cell sensitivity to platinum drugs. Mechanistically, our results demonstrate that miRNA221_5p epigenetically regulates RAD18-mediated DNA damage tolerance and homologous recombination repair and could be a novel therapeutic to overcome OC chemoresistance. Collectively, our studies identify a novel chemotherapy-induced epigenetic modulator in OC therapeutic resistance and offer novel miRNA 221-5p-mediated therapeutic intervention for the treatment of chemoresistant OC and to prevent disease recurrence. Citation Format: Tasmin Rahman Omy, Chinnadurai Mani, Komaraiah Palle, Mark Reedy. Epigenetic-miRNA regulatory circuit confers ovarian cancer chemoresistance through RAD18-mediated DNA damage tolerance and repair signaling. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6106.