Abstract 1703: Molecular drivers of enzalutamide resistance in prostate cancer: insights into CYP3A5 and associated pathways

Abstract Prostate cancer (PC) disproportionately affects Black/African American (AA) men, who experience higher incidence rates, more aggressive disease, and worse outcomes compared to non-Hispanic White Americans (NHWA). CYP3A5, a cytochrome P450 enzyme, is expressed at higher levels in individuals carrying the *1 variant, prevalent in AAs, compared to the *3 variant, more common in NHWA. Elevated CYP3A5 expression in AAs has been associated with aggressive prostate cancer phenotypes, potentially due to its role in activating androgen receptor (AR) signaling and promoting crosstalk with Wnt signaling pathways. Resistance to AR-targeted therapies, such as enzalutamide, remains a major challenge in metastatic castration-resistant prostate cancer (mCRPC), particularly in aggressive disease subtypes. To investigate mechanisms underlying enzalutamide resistance, we generated resistant PC cell lines of NHWA origin (low CYP3A5-LNCaP) and AA origin (high CYP3A5-MDAPCa2b). In resistant MDAPCa2b cells, RT2 androgen receptor profiler arrays revealed upregulation of MME, SGK1, SNAI, and STEAP, genes implicated in Wnt pathway regulation (SGK1), epithelial-to-mesenchymal transition (SNAI), and enhanced proliferation and migration (STEAP). Additionally, tumor suppressors and regulatory genes, including ADAMTS1, KLK4, MT2A, NDRG1, and TIPARP, were significantly downregulated, suggesting reduced ECM remodeling, oxidative stress responses, and DNA repair capacity in resistant cells. Importantly, CYP3A5 expressions were significantly elevated in resistant MDAPCa2b cells but remained unchanged in resistant LNCaP cells, highlighting a potential link between high CYP3A5 expressions and resistance mechanisms. The upregulation of SGK1, SNAI, and STEAP, alongside the downregulation of ADAMTS1, KLK4, MT2A, NDRG1, and TIPARP, suggests that resistance to enzalutamide involves AR and Wnt signaling, EMT, and loss of tumor suppressive functions. These findings support the hypothesis that the *1 CYP3A5 variant in AAs drives aggressive disease and therapeutic resistance, providing a molecular basis for observed clinical disparities and potential pathways for targeted intervention. Citation Format: Imran Khan Mohammed, Ranjana Mitra. Molecular drivers of enzalutamide resistance in prostate cancer: insights into CYP3A5 and associated pathways [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 1703.