Abstract A026: BMX inhibition reverses HSD3B1-driven resistance in prostate cancer

Abstract

Abstract Background: Prostate cancer is the second leading cause of cancer-related death in men in the United States and is dependent on androgens and androgen receptor (AR) activation. Androgen deprivation therapy (ADT) is the mainstay treatment, but it as well as next-generation treatments eventually fail. Disease then progresses as castration-resistant prostate cancer (CRPC), which is driven by reactivation of the androgen-AR axis. 3β-hydroxysteroid dehydrogenase-1 (3βHSD1) catalyzes the rate-limiting step for potent androgen synthesis from adrenal-derived precursors, thereby stimulating CRPC. HSD3B1, which encodes for 3βHSD1, has a common missense-encoding germline variation that enhances conversion from adrenal DHEA to potent androgens. Clinical studies demonstrate that this “adrenal-permissive” HSD3B1 genotype confers more rapid progression on ADT, and recent studies show that overall survival is shorter in patients with the adrenal-permissive genotype who are treated with ADT + enzalutamide. The Etk/BMX kinase may be involved in the development and progression of CRPC. We sought to determine whether phosphorylation of 3βHSD1 is required for its activation and that the necessary kinase could be a potential target. Methods: In prostate cancer lines, mouse xenograft models, and fresh patient prostatectomy tissues, mass spectrometry and HPLC were used to identify steroid metabolites. Genetic and pharmacological methods were used to identify inhibition of BMX-mediated 3βHSD1 phosphorylation in CRPC. Results: BMX inhibition suppressed castration-resistant prostate cancer through targeting 3βHSD1 phosphorylation. 3βHSD1 transcription level and enzyme activity were induced in enzalutamide-resistant prostate cancer cell lines. 3βHSD1 and SF-1 transcription levels were positively correlated in prostate adenocarcinoma (TCGA database). BMX inhibition by zanubrutinib suppressed enzalutamide resistance induced 3βHSD1 enzyme activity. Conclusions: BMX promotes CRPC by regulating 3βHSD1 phosphorylation. BMX inhibition has potential as a new therapy to optimize CRPC treatment. Citation Format: Xiuxiu Li, Michael Berk, Christopher Goins, Mohammad Alyamani, Yoon-Mi Chung, Chenyao Wang, Monaben Patel, Nityam Rathi, Ziqi Zhu, Belinda Willard, Shaun Stauffer, Eric Klein, Nima Sharifi. BMX inhibition reverses HSD3B1-driven resistance in prostate cancer [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 A026.