Abstract 335: Variable off-target effects of clinically advanced PARP inhibitors

Abstract

Abstract High-grade serous ovarian carcinoma (HGSOC) is the most common subtype of ovarian cancer with low 5-year survival rates. Inhibitors of poly (ADP-ribose) polymerase (PARP) are promising novel agents that uniquely target HGSOCs with DNA repair deficiencies. The majority of patients with DNA repair proficient HGSOCs do not respond to PARP inhibitor monotherapy, highlighting the need for novel treatment approaches for these women. The goal of this study was to expand the patient population that could benefit from PARP inhibition by identifying the off-target effects that are favorable in combination with CHK1 inhibitors among the five most clinically advanced PARP inhibitors. Cell cycle and western blot analysis revealed that the four most potent PARP trappers (rucaparib, olaparib, niraparib, and talazoparib) have a strong effect on the cell cycle. The PARP trappers in particular activated CHK1 through phosphorylation at the serine 345 residue, decreased total protein levels of CDC25C, and arrested cells in the S/G2 phase of the cell cycle. These results were not observed after treatment with veliparib, the least potent PARP trapper. We created phospo-CHK1 mutants to confirm CHK1 activation at serine 345 and to further investigate whether potent PARP trappers activate CHK1 on serine 317, another residue that is also phosphorylated in response to replication stress. The data suggest that PARP trappers activate CHK1 at both the serine 317 and 345 phosphorylation sites. Next, we examined whether PARP inhibition-induced activation of CHK1 is a determinant of synergy between PARP and CHK1 inhibitors. We exposed one of our established BRCA wild-type, TP53 mutant HGSOC patient-derived xenograft models to a PARP1 inhibitor (veliparib or talazoparib) or to the CHK1 inhibitor (MK-8776) or a combination of PARP and CHK1 inhibitors. CHK1 inhibition slightly increased sensitivity to talazoparib compared to single agent therapy. However, the tumor volume was significantly reduced by the combination of CHK1 inhibition and veliparib treatment compared to either single agent alone. This study suggests that there are off-target cell cycle effects that vary among the five most clinically-advanced PARP inhibitors that likely influence the response to combinatorial treatment. We propose the use of PARP and CHK1 inhibition as a strategy for HGSOC patients who would otherwise have minimal benefit to PARP inhibitor monotherapy. Citation Format: Monica E. Wielgos, Jay Patibandla, Michelle Firlit, Elke Van Oudenhove, Paulina Cybulska, Petar Jelinic, Douglas A. Levine. Variable off-target effects of clinically advanced PARP inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 335.