Abstract 2110: Platinum-inducedBRCA1 promoter DNA hypermethylation and altered metabolic profile promotes chemoresistance in ovarian cancer

Abstract

High grade serous ovarian cancer (HGSOC) is the most common and aggressive type of ovarian cancer (OC). Platinum resistance is a common occurrence in HGSOC leading to tumor relapse and patient mortality. Multiple mechanisms contribute to platinum resistance in OC, including enrichment of ovarian cancer stem cells (OCSCs), which is observed in relapsed tumors. Platinum treatment activates the DNA damage response (DDR) and the DNA repair protein BRCA1 is an OC susceptibility factor. In our study, we demonstrate that platinum treatment induces a decrease in BRCA1 levels that leads to an increase in activity of ALDH, an OCSC marker. In a parallel pathway that is associated with G2/M arrest, platinum treatment also induces an increase in NAMPT expression and NAD+ levels, the cofactor required for ALDH activity. BRCA1 is repressed through platinum-induced promoter DNA hypermethylation. Importantly, combination of platinum with decitabine, a DNA methyltransferase (DNMT) inhibitor, prevents the platinum-induced increase in OCSCs. This study uniquely provides preclinical support for the use of DNMT inhibitors in the neoadjuvant setting in combination with platinum treatment for OC patients. Citation Format: Riddhi Sood, Sikai Xiao, Shruthi Sriramkumar, Christiane Hassel, Kenneth Nephew, Heather O'Hagan. Platinum-inducedBRCA1 promoter DNA hypermethylation and altered metabolic profile promotes chemoresistance in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2110.