Abstract B067: CRM1 inhibitor selinexor induces DNA damage repair-related vulnerability in prostate cancer cells

Abstract

Abstract Background: Advanced metastatic prostate cancer is the second leading cause of death in men in the United States. Androgen deprivation therapy has been used as a front-line therapy; however, despite initial success, it fails subsequently and results in the development of castration-resistant prostate cancer. Due to these unmet therapeutic needs, there is an urgency to identify novel targets to develop next-generation therapeutics. Chromosome region maintenance 1 (CRM1) is one of the seven members of mammalian export proteins that function to export the proteins using nuclear export signal (NES). Several tumors, including prostate cancer, overexpress CRM1 to efflux tumor suppressor proteins to the cytoplasm and exhibit dysregulated nuclear export. CRM1-mediated export can lead to functional inactivation of p53, cyclinD1, p16, p21, and p27. Essential DNA repair proteins such as Rad51 and BRCA1 exhibit leucine-containing hydrophobic residues rich in NES and are known to be shuttled by CRM1. Based on this, we hypothesize that CRM1 inhibition may affect the expression, kinetics, localization, and stability of DNA repair network proteins. Methods: Androgen receptor-positive and negative prostate cancer cells were treated with Selinexor. The dose of the drug and duration was dependent on the endpoint measurement. Cell death was monitored using MTT assay and western blot measurement of cleaved PARP. Total RNA and cell lysate were collected to measure the relative levels of BRCA-1, RAD51, p53, and other members of the DNA repair pathway (HR and NHEJ). DNA damage was estimated using the number of micronuclei and immunofluorescence staining for γ-H2AX and COMET assay. Results: Selinexor treatment in prostate cancer cells affects the functioning of the DNA repair network and can be combined with inhibitors of DNA repair proteins. Citation Format: Rajendra Kumar, Janet Mendonca, Yuhan Yang, Abhishek Shetty, Lillian Wilson, Kavya Boyapati, Deven Topiwala, Keerti Soundappan, Eleni Panagopoulos, Michael Carducci, Sushant Kachhap. CRM1 inhibitor selinexor induces DNA damage repair-related vulnerability in prostate cancer cells [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B067.