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BMX Controls 3βHSD1 and Sex Steroid Biosynthesis in Cancer - Beyond the Abstract

The androgen axis and androgen signaling is probably the most important therapeutic target in prostate cancer.1 Androgens are gonadal and extragonadal in origin. Use of medical castration (ADT), adrenal androgen synthesis inhibition (abiraterone), and potent androgen receptor (AR) antagonists (enzalutamide, apalutamide, darolutamide), all have clinical benefit in a variety of prostate cancer disease states. However, the development of resistance to all of these therapies is a major problem and the AR frequently re-emerges as a resistance driver. Stimulation of the AR ligand-binding domain is one obvious way in which tumors can elicit treatment resistance.

Half of the men with prostate cancer inherit an activating missense in the enzyme that catalyzes the first and rate-limiting step in the conversion of adrenal precursor steroids to dihydrotestosterone (DHT). This form of the 3β-hydroxysteroid dehydrogenase-1 (3βHSD1) enzyme is encoded by the “adrenal-permissive” HSD3B1(1245C) allele which increases potent androgen biosynthesis from adrenal precursor steroids. The HSD3B1(1245C) allele has been genetically linked to poor clinical outcomes after ADT, as well as the newer generation of potent hormonal therapies.2 However, there is no known clinical method of blocking the activity of the 3βHSD1 enzyme.

A recent paper from our group identifies a phosphorylation site on 3βHSD1 that is required for cellular enzyme activity and androgen biosynthesis.3 The BMX kinase is necessary for phosphorylation of tyrosine 344 of 3βHSD1. Genetic or pharmacologic inhibition of BMX blocks androgen biosynthesis and castration-resistant prostate cancer (CRPC) xenograft growth in vivo. Fortuitously, BMX is a close relative of the BTK kinase, which has several inhibitors in the clinic. These inhibitors frequently overlap in activity against both BTK and BMX. These preclinical data have led to the launch of the MAVERICK clinical trial (NCT05361915) through the Prostate Cancer Clinical Trials Consortium, which selects men with CRPC based on HSD3B1 genotype and tests the combination of abiraterone plus the BMX inhibitor abivertinib. More broadly, this work establishes an entirely new proof-of-concept for blockade of sex-steroid-dependent cancers.

Written by: Nima Sharifi, MD, Director, Genitourinary Malignancies Research Center, Kendrick Family Endowed Chair for Prostate Cancer Research, Cleveland Clinic

References:

  1. Desai, K., McManus, J. M. & Sharifi, N. Hormonal Therapy for Prostate Cancer. Endocr Rev 42, 354-373, doi:10.1210/endrev/bnab002 (2021).
  2. Michael, P., Roversi, G., Brown, K. & Sharifi, N. Adrenal steroids and resistance to hormonal blockade of prostate and breast cancer. Endocrinology, doi:10.1210/endocr/bqac218 (2022).
  3. Li, X. et al. BMX controls 3betaHSD1 and sex steroid biosynthesis in cancer. J Clin Invest 133, doi:10.1172/JCI163498 (2023).
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