Abstract 3816: Corilagin could help to overcome PARP inhibitor resistance by inhibiting ERK signaling pathways

Abstract

Abstract We have identified that Corilagin is a major anti-tumor active component extracted from a well-known hepatoprotective and antiviral medicinal herb, Phyllanthus niruri L. Our previous work found that Corilagin inhibited the growth of ovarian cancer cells via TGF-β/AKT/ERK signaling pathways. Corilagin also sensitizes Paclitaxel and Carboplatin by primarily inhibiting Snail-glycolysis pathways. Recently, we have investigated if Corilagin could give a help to overcome poly ADP ribose polymerase (PARP) inhibitors (PARPi) resistance in ovarian cancer cells. As we knew, PARP inhibitors are DNA repair drugs, have been approved for ovarian cancer therapy, but drug resistance is a faced problem, combination therapy may give helps. In this study, two pairs of PARPi sensitive/resistant cells: A2780CP/A2780CP_R and UMB1.289/UMB1.289_R (Sci Transl Med. 2017; 9:392) were used. Cells were cloned again and confirmed their sensitivities to PARPi. The IC50 of PARPi-BMN673 is 0.02μM to A2780CP, &gt 10μM to A2780CP_R, 0.12μM to UMB1.289 and 60μM to UMB1.289_R. The combination assays showed Corilagin had almost equally cytotoxic activities to these two pairs and had synergistic effects with BMN673 to A2780CP_R and UMB1.289_R . Using CulcuSyn, the combination indexes (CI) presented at IC50 are 0.17365 and 0.62787 in A2780_R and UMB1.289_R, respectively. Signaling analysis found that PARPi did down-regulate the expression levels of PARP and up-regulate of pH2AX, PARPi only inhibited pERK activity in sensitive cells, but not in resistant cells. In contrast, Corilagin did not have DNA repair function, but it inhibited pERK activity in both sensitive and resistant cells. In summary, we demonstrate that combined treatment with Corilagin and PARPi evokes synergistic cytotoxic effects in two pairs of ovarian cancer cell models. Corilagin is an herb medicine with lower toxic effects to normal cells, especially hepatoprotective, which could be an ideal complimentary medicine when combinating with PARPi in ovarian cancer therapy. Citation Format: Baoxin Luan, Hongbo Zhao, Robert C. Bast, Jr., Zhen Lu, Yinhua Yu. Corilagin could help to overcome PARP inhibitor resistance by inhibiting ERK signaling pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3816.