Abstract 1676: POLB as a novel synergistic target for combination therapy with niraparib

Abstract To identify novel drug targets for combination therapy with PARP inhibition, we performed a comprehensive niraparib x genome-wide (gw) CRISPR combination screen across 65 cancer cell lines representing multiple tumor indications. POLB was identified as a top synergy hit with niraparib, and was also confirmed by a targeted niraparib x CRISPR in vivo screen focusing on DNA damage repair pathways. POLB is a critical factor for the base excision repair (BER) pathway. Thus, we hypothesized that POLB loss results in disruption of the BER pathway, leading to accumulation of DNA damage in the presence of PARP inhibitor. Consistent with this hypothesis, POLB CRISPR knockout (KO) significantly increased niraparib sensitivity in DLD1 and HeLa cancer cell lines. This sensitivity was further amplified when single-strand DNA breaks were induced. Rescue experiments revealed that the lyase activity of POLB is a major driver of the synergy with niraparib. Mechanistic studies validated the hypothesis that POLB loss increases γH2AX foci and PARP1 trapping, indicating increased DNA damage. Our findings underscore POLB as a promising therapeutic target for combination with Niraparib, offering a potential avenue for enhancing cancer treatment efficacy. Citation Format: Joe Z. Wang, Hunain Alam, Rajarshi Choudhury, Ning Sun, Euan Stronach, David Alvarado, Benjamin Schwartz, Kelly Choi. POLB as a novel synergistic target for combination therapy with niraparib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1676.