Abstract A31: The two most potent PARP inhibitors increase expression levels of innate immune response genes in BRCA wild-type HGSC tumors
Authors: Monica Wielgos-Bonvallet, Danhui Weng, Petar Jelinic, Douglas A. Levine
Journal: Clinical Cancer Research (2020)

Abstract Background: Poly (ADP-ribose) polymerase (PARP) inhibitors have transformed treatment of ovarian cancer in the past decade. Most of the currently active PARP inhibitors have similar ability to inhibit PARP’s enzymatic activity. However, it has been previously reported that velipairb, rucaparib, olaparib, niraparib, and talazoparib vary in their PARP trapping potency levels. Veliparib was also characterized to be mainly a catalytic inhibitor while the other four drugs were determined to be both PARP trappers and catalytic inhibitors, with talazoparib being the most potent PARP trapper. Responses in many patients with HGSC tumors are limited, particularly those women without known mutations in BRCA1 or BRCA2. Recently, PARP inhibitors have been reported to influence innate immune responses. For these reasons, there are ongoing clinical trials testing the safety and efficacy of PARP inhibitors in combination with various immune checkpoint inhibitors. The objective of this study is to compare the effect of the five most clinically active PARP inhibitors on type 1 interferon regulated genes and the PD-L1 gene. Methods: Two high-grade serous ovarian cancer cell lines were used in this study: CAOV3 (TP53 mutant) and OVCAR3 (TP53 mutant, CCNE1-amplified, and EMSY-amplified). The cell lines were treated for 48 hours with the PARP inhibitors listed above as well as a vehicle control (DMSO). Gene expression was measured using TaqMan assays. CXCL10 (IP-10) protein expression levels were determined via an ELISA assay. Summary of the Data: Talazoparib upregulated CXCL10 gene expression in both OVCAR3 and CAOV3 cell lines. These results were translated to the protein level, as we observed an increase in IP-10 protein expression levels after talazoparib treatment in the OVCAR3 cell line. IP-10 protein levels were also significantly increased when treated with the second most potent PARP inhibitor, niraparib. A statistically significant effect was not observed after treatment with the three other PARPis. Futhermore, CD274 (PD-L1) gene expression levels were significantly increased after talazoparib and not veliparib treatment in the CAOV3 cell line. Conclusions: Our data suggest that there are distinct effects exhibited among PARP inhibitors on innate immune pathways. The two most potent PARP inhibitors, niraparib and talazoparib, had the greatest effect on these pathways, specifically in BRCA wild-type HGSCs, compared to the three other drugs. These finding support the idea that we need to define the best PARP inhibitor to use in future clinical trials when combining this group of anticancer agents with immune checkpoint inhibitors. Citation Format: Monica Wielgos-Bonvallet, Danhui Weng, Petar Jelinic, Douglas A. Levine. The two most potent PARP inhibitors increase expression levels of innate immune response genes in BRCA wild-type HGSC tumors [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A31.