Abstract 3970: PARP inhibitors increase expression of Type I interferon regulated genes mainly through trapping

Abstract

Abstract Background: Currently, there are multiple ongoing clinical trials testing the efficacy of various poly (ADP-ribose) polymerase (PARP) inhibitors in combination with immune checkpoint blockade across many cancer types. However, there is no rationale as to which PARP inhibitor is best to use in these studies. Two PARPis (rucaparib and talazoparib) have been reported to activate IFN signaling genes through the stimulator of interferon genes (STING) pathway. The objective of this study is to characterize the effect of all clinically active PARPis on Type I interferon (IFN) regulated genes. We also aim to identify whether this effect is dependent on CHK1, which we have previously reported to be activated by PARP trappers (rucaparib, olaparib, niraparib, and talazoparib) and not by the mainly catalytic inhibitor (veliparib). Methods: CCL5 and CXCL10 gene expression levels were measured using qRT-PCR in 293T after two days of treatment with the PARP inhibitors (velipairb, rucaparib, olaparib, niraparib, and talazoparib). CXCL10 mRNA levels were also measured in HGSOC BRCA wild-type cell lines (OVCAR3 and CAOV3) after two days of treatment with veliparib and talazoparib. We also measured CCL5 and CXCL10 expression after veliparib and niraparib treatment in 293T cells with stable CHK1 overexpression. Results: The four PARP trappers consistently increased CCL5 and CXCL10 expression in 293T cells. Although, veliparib had little to no effect on the expression of these two genes as compared to the other four PARPis. CXCL10 mRNA levels were significantly upregulated after talazoparib treatment (p<0.01) but not affected after veliparib treatment in CAOV3 cells. Similarly, an increase in CXCL10 gene expression was observed in OVCAR3 cells (p<0.05). Although, veliparib also had a modest but not significant effect on CXCL10 levels. CCL5 and CXCL10 gene expression consistently increased when treated with niraparib in 293T cells with stable CHK1 overexpression. This same effect was not observed after veliparib treatment in 293T cells that stably overexpressed CHK1. Conclusions: Our results suggest that all PARP trappers promote expression of IFN Type I regulated genes which may be dependent on CHK1 expression. These findings may better define the most ideal PARP and immune checkpoint inhibitor combination. Citation Format: Monica E. Wielgos, Petar Jelinic, Douglas A. Levine. PARP inhibitors increase expression of Type I interferon regulated genes mainly through trapping [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 3970.