Abstract PR006: Elucidating the effect of PARP inhibitors on MMEJ-mediated DNA repair

Abstract

Abstract First-line maintenance treatment for homologous recombination (HR)-deficient (HRD, e.g., BRCA1/2 mutations) cancers includes poly ADP-ribose inhibitors (PARPi, e.g., olaparib, niraparib). PARPi are lethal through multiple mechanisms, including PARP trapping and PARP activity inhibition, which both destabilize the replication fork machinery in the absence of BRCA1/2. However, only 50% of HRD tumors respond to PARPi treatment due to intrinsic resistance and of those that respond, most tumors eventually relapse due to acquired drug resistance. Because MMEJ is essential in HRD-cancers, it has emerged as a promising target to combat PARPi resistance, with POLQ inhibitors currently in clinical trials. Thus, understanding the interplay between MMEJ and PARP inhibitors is critical. While PARP1 is proposed to promote MMEJ, PARP regulates numerous aspects of DSB repair, and therefore its overall impact on MMEJ levels remains unclear. For instance, the effect of PARP inhibition on DSB end-resection, a critical step of MMEJ, remains controversial. Utilizing a DNA repair reporter, we assessed MMEJ levels following treatment with various PARP inhibitors, including those with minimal PARP trapping activity. Remarkably, we find that PARP inhibition systematically leads to elevated MMEJ levels in a POLQ-dependent fashion. Furthermore, PARP inhibition also induces higher MMEJ levels in cells treated with NHEJ inhibitors as well as in HR-deficient cells, including an HRD ovarian cancer cell line (PEO1, BRCA2mut). Therefore, this MMEJ upregulation cannot be simply attributed to a PARPi-mediated suppression of NHEJ or HR activity. Taken together, our data suggests that the overall effect of PARP inhibitors may lead to upregulation, rather than suppression, of MMEJ activity. We are currently assessing the contribution of PARP1 and PARP2 in MMEJ regulation and are testing whether PARPi also increase MMEJ levels at sites of replication induced DSBs. We hypothesize that PARPi could upregulate MMEJ through modulating DSB end-resection. This insight bears significant implications for the development of combination therapies of MMEJ and PARP inhibitors in treating HRD cancers. Citation Format: Raquel Ortega, Nausica Arnoult, Benjamin G Bitler. Elucidating the effect of PARP inhibitors on MMEJ-mediated DNA repair [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr PR006.