Abstract 4093: Drug combinations that can overcome resistance to PARP inhibitor therapy for BRCA1-associated breast cancer

Abstract

Abstract Triple negative breast cancer (TNBC) represents approximately 10–15% of all breast cancers and has a poor outcome as it lacks a receptor target for therapy. Poly (ADP-ribose) polymerases inhibitors (PARPi) drugs have demonstrated some effectiveness in treating BRCA1 or BRCA2 mutated breast and ovarian cancers but resistance to PARPi is common. Published results found that resistance to Olaparib, a PARPi, can be due to downregulation of EMI1 and the consequent upregulation of the RAD51 recombinase. Using a tissue culture-based cell viability assay, we extended those observations to another PARPi and to other chemotherapy drugs that affect DNA repair or the cell cycle. As we expected, EMI1 downregulation resulted in resistance to another PARPi drug, Talazoparib. EMI1 downregulation also led to resistance to other cytotoxic drugs, Cisplatin and CHK1 inhibitor. Surprisingly, EMI1 downregulation also led to resistance to a MEK inhibitor, though this inhibitor blocks cells in G1 phase of the cell cycle and would not be expected to be sensitive to EMI1 levels. Notably, increasing the RAD51 protein expression can mimic the EMI1 downregulation and lead to resistance to different PARPis and the other cytotoxic drugs. This result suggests that the key downstream effect of EMI1 downregulation is increasing the concentration of RAD51 protein in the cell. We found that combining CHK1 inhibitor with Olaparib results in cell death in a dose specific manner. This combination therapy may be a means to overcome the PARPi resistance in BRCA1-deficient TNBC cells. Citation Format: Dina Mohamed Abd El Aziz Moustafa, Maha Abd Elwahed, Hanaa El Said, Jeffrey Parvin. Drug combinations that can overcome resistance to PARP inhibitor therapy for BRCA1-associated breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4093.