Abstract 890: DNA deaminase APOBEC3B regulates theresponse to PARP inhibitors of epithelial ovarian cancer stem cells

Abstract

Abstract The most aggressive types of ovarian cancer is high-grade serous ovarian cancer (HGSOC), and the 5-year survival is less than 20%. Relapsed HGSOC patients often have enrichment of cancer stem cells (CSCs) with enhanced pro-survival and self-renewal capacity, suggesting a potential vulnerable population for effective targeted therapies with less toxicity. APOBEC3 proteins are a family of primate-specific DNA deaminases that catalyze cytidine to uracil (C-to-U) on single-strand DNA thereby introducing C-to-T/G point mutations. This important DNA modification is abundant in a wide array of cancer types including HGSOCs. However, the prevalence and significance of A3-induced DNA deamination in HGSOC CSC is currently unknown. We recently discovered that CSCs maintain a low A3-induced mutation burden. Using patient-sample derived spheroid culture and HGSOC cell lines, we found A3B was the only A3 members differentially expressed between CSC and non-CSC and the expression was significantly reduced in CSCs. In addition, inhibition of A3B leads to elevated frequency of CSCs and enhanced expression of the stemness factors. Important, our data suggest that DNA deaminase activity of A3B leads to induction of DNA damage thereby sensitizing HGSOC CSCs to PARPi. These novel insights suggest that DNA deamination plays a fundamental role in CSC biology and also raises the possibility that A3B activation may sensitize HGSOC CSCs to PARPi by promoting DNA damages. Citation Format: Jane isquith, Jessica Pham, Robert Phavong, Maria Rivera, Kathleen Fisch, Catriona Jamieson, Michael McHale, Ramez Eskander, Qingfei Jiang. DNA deaminase APOBEC3B regulates theresponse to PARP inhibitors of epithelial ovarian cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 890.