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Background: Prostate cancer continues to show challenges in disease management and ultimately leads to advanced disease with poor survival. These unmet needs, despite recent advances, are leading researchers to identify novel targets to develop next-generation therapeutics. Considerable evidence from the published reports and TCGA database analysis indicates that CRM1, which functions as a nuclear export protein, amplifies prostate cancer, resulting in dysregulated nuclear export machinery. This dysregulation is also seen to correlate with mislocalization of p53, FOXO-1, and 3a, cyclinD1, p16, p21, and p27 in prostate cancer. Besides these mislocalized proteins, key DNA repair pathway members such as BRCA1 and Rad51 exhibit a nuclear export signal (NES) and are putative CRM1 cargoes. Nuclear-cytoplasmic shuttling of these repair proteins may play an essential role in repairing damaged DNA. We hypothesize that inhibition of CRM1 would result in defective DNA repair through disruption of nuclear-cytoplasmic shuttling of important repair protein cargoes. Methods: PCa cells (both AR-positive and negative lines) were treated with Selinexor to estimate the subtoxic doses. Cell lysates and total mRNA were collected to evaluate the relative levels of BRCA-1, RAD51, p53, ATM, ATR transcripts, and proteins. Activation of the DNA damage pathway was measured through a phosphorylated form of these proteins, and functional assessment of homologous recombination(HR) was measured through an HR sensor plasmid construct. Results: Treatment of PCa cells with Selinexor affected expression, localization, and kinetics of DNA repair leading to unrepaired DNA and induced apoptosis. Citation Format: Rajendra Kumar, Janet Mendonca, Kavya Boyapati, Yuhan Yang, Deven Topiwala, Suthicha Kanacharoen, Keerti Soundappan, Lillian Wilson, Eleni Panagopoulos, Michael Carducci, Sushant K. Kachhap. Exploring the role of CRM1 in DNA repair pathway in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1505.