DNA Methyltransferase inhibitors in Combination with PARP inhibitors Generate Synthetic Lethality in BRCA-proficient Ovarian Cancer

Abstract

Approximately 10% of Epithelial ovarian cancer (EOC) patients have BRCA mutations and are treated with FDA approved poly (ADP-ribose) polymerase (PARP) inhibitors. While some patients with BRCA wild-type EOC have shown a response, the majority of BRCA mutated EOC respond to PARPi therapy. The standard therapy for EOC patients is platinum-based chemotherapy which often leads to resistance to this treatment. Therefore, new therapies are essential for the improvement of EOC treatment. In this study we will investigate the role of low-dose epigenetic therapy in reprograming the DSB repair response to potentially induce a "BRCAness" effect that sensitizes EOC cells to PARPi. We show that 5-AZA reprograms epigenome by changing the gene expression in DNA repair genes which lead to BRCAness and results in impaired HR-mediated repair. Lastly, we will determine whether the downregulation of FANCD2, is responsible for sensitization of EOC cell to PARPi therapy that results in increased cytotoxicity.