Abstract 4675: Novel combination therapy of DNA methyltransferase inhibitor guadecitabine (SGI-110) and PARP inhibitor talazoparib (BMN-673) for BRCA-proficient high-grade serous ovarian cancer

Ovarian cancer recurrence has been shown to be associated with increased DNA damage response (DDR) mediated by poly-(ADP)-ribose polymerase 1/2 (PARP1/2), which can be therapeutically targeted by PARP inhibitors (PARPi). PARPi are indicated for platinum-responsive, BRCA-mutated high-grade serous ovarian cancer, but most ovarian cancer patients have BRCA-proficient disease. Our previous studies support a role for DNA methylation in chemoresistant ovarian cancer mediated by the enzyme DNA methyltransferase 1 (DNMT1), and report on a functional role for DNMT1 in DNA damage repair. We therefore hypothesized that combining a DNMTi and PARPi will impair BRCA-mediated DDR, resulting in cytotoxicity in ovarian cancer cells. A panel of ovarian cancer cell lines (A2780, platinum sensitive, BRCA1/2-wild type; A2780-cp and HeyC2, platinum resistant, BRCA1/2-wild type; high-grade serous Kuramochi, platinum resistant, BRCA2 mutant) was examined for cell growth using colony formation assays after treatment with DNMTi guadecitabine (low dose, 20-100nm) and PARPi talazoparib (1-10nm), alone or in combination. While talazoparib alone only marginally reduced colony formation in all cell lines (dose-dependent effect), combining guadecitabine with talazoparib further decreased (P 80%; P 60%) and tumor weight (~70%) compared to control, respectively. In summary, combining a hypomethylating agent with a PARP inhibitor results in enhanced cytotoxicity in high-grade serous ovarian cancer cell lines harboring either wild type- or mutant-BRCA, indicating that the talazoparib-guadecitabine drug combination is effective regardless of BRCA-mediated DDR and may represent an effective treatment regimen for BRCA-related cancers. Citation Format: Nicholas Pulliam, Pietro Taverna, John Lyons, Kenneth P. Nephew. Novel combination therapy of DNA methyltransferase inhibitor guadecitabine (SGI-110) and PARP inhibitor talazoparib (BMN-673) for BRCA-proficient high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4675. doi:10.1158/1538-7445.AM2017-4675