Abstract 316: Subcellular localization of PARP1 by protein kinase D1 modulated cellular response to olaparib.

Abstract DNA damage and repair play a dual role in cancer: unrepaired lesions drive mutations and tumor growth, while repair pathways enable cancer cells to resist therapies like chemotherapy and radiation. PARP1 detects DNA breaks, adds poly(ADP-ribose) to target proteins, and recruits repair factors, with localization mainly in the nucleus but extending to other compartments under certain conditions. Inhibition of PARP1 prevents DNA repair, leading to cancer cell death, and FDA-approved PARP1 inhibitors show efficacy in metastatic castration-resistant prostate cancer, though dose-limiting toxicities reduce effectiveness. This study examines Protein kinase D1 (PrKD1) as a modulator of PARP1 and its impact on sensitivity to PARP inhibition. Using prostate cancer cell lines with altered PrKD1 expression (LNCaP, LNCaP ShPrKD1, C4-2, and C4-2 PrKD1), we found that PrKD1 overexpression increased sensitivity to Olaparib (PARP1 inhibitor), while downregulation conferred resistance. Pharmacological inhibition of PrKD1 with Compound-10 also enhanced Olaparib sensitivity. Co-immunoprecipitation studies suggest PrKD1-PARP1 interaction in subcellular fractionations, and PrKD1 transfection in C4-2 prostate cancer cells increased PARP1 membrane localization. Compound-10 treatment in prostate cancer cells and PDX models represented elevated PARP1 expression. In-silico modeling also identified a potential PrKD1 binding site adjacent to PARP1 WGR (tryptophan-glycine-arginine-rich) domain. Overall, PrKD1 emerges as a novel PARP1 regulator. Co-targeting PARP1 using Olaparib and Compound-10 may improve efficacy at lower doses, enhance tolerability, and expand therapeutic options. Based on the in-vitro, in-vivo and in-silico studies we may suggest the interaction between PrKD1 and PARP1 in subcellular membrane compartments. The discovery of PARP1 at the membrane opens new opportunities for theragnostic applications. Citation Format: Sanjeev Shukla, Joseph McGrath, Robert Willis, Arjun Venkatesh, Jean-Pierre Kanumuambidi, Reynier Rodriguez-Rosales, Mario Mietzsch, Robert McKenna, K.C. Balaji. Subcellular localization of PARP1 by protein kinase D1 modulated cellular response to olaparib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 316.