Abstract 4415: Nuclear receptor liver receptor homolog-1 (LRH-1) contributes to enzalutamide-resistance in castration-resistant prostate cancer

Abstract Introduction: Prostate cancer is the most common cancer in males worldwide and the second leading cause of cancer-related deaths. Targeting androgen signaling through androgen deprivation therapy (ADT) is an important treatment option for prostate cancer, although the majority of patients eventually progress to castration-resistant prostate cancer (CRPC). Several second-generation anti-androgen drugs including enzalutamide are conventionally used for CRPC patients. However, resistance to potent anti-androgen treatments inevitably develops in prostate cancer patients. Liver receptor homolog-1 (LRH-1, NR5A2) is a member of nuclear receptor super family, which is characterized to be involved in the regulation of steroids, bile acid and cholesterol homeostasis, glucose metabolism and cell proliferation. Our previous study has found that LRH-1 can promote the intratumoral androgen biosynthesis to support the growth of CRPC cells. Meanwhile, our unpublished results showed that LRH-1 was negatively regulated by androgen receptor (AR) signaling pathway, suggesting that LRH-1 expression may play roles in anti-androgen drug resistance, especially in enzalutamide-resistant prostate cancer. Methods: Prostate cell line 22Rv1 is characterized as an enzalutamide-resistant prostate cancer cell line. CCK8 assay was performed to measure the viability of cells treated with enzalutamide and LRH-1 antagonist (ML180). ChIP-qPCR was performed to validate the potential binding sites of LRH-1 in AR promoter. Luciferase reporter gene assay using constructed reporters driven by different lengths of AR promoter and various LRH-1 variant mutants was performed to validate the activation of AR promoter by LRH-1. Results: Public dataset analysis revealed that high LRH-1 expression was associated with poor disease-free survival rate. LRH-1 expression was elevated after long-term enzalutamide treatment. We found that knock-down of LRH-1 attenuated cell viability of enzalutamide-resistant cells and LRH-1 antagonist ML180 could reverse the drug resistance in prostate cancer cells. Furthermore, we demonstrated that LRH-1 could bind to and activate AR promoter region and induce AR expression, suggesting a possible mechanism on the occurrence of enzalutamide resistance in CRPC. Conclusion: LRH-1 could contribute to the induction of enzalutamide resistance in prostate cancer via specific regulation of AR gene. Our results also indicated that targeting LRH-1 could be a potential therapeutic management for enzalutamide resistance in CRPC. (This work is supported by RGC-Granted Research Fund (Project number: 14107623), Hong Kong Research Grants Council.) Citation Format: Tiantian Gao, Franky Leung Chan. Nuclear receptor liver receptor homolog-1 (LRH-1) contributes to enzalutamide-resistance in castration-resistant prostate cancer [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 4415.