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HSD3B1 status as a biomarker of androgen deprivation resistance and implications for prostate cancer

Nature Reviews Urology volume 15, pages 191196 (2018) | Download Citation

Abstract

Patients with advanced prostate cancer who receive androgen deprivation therapy (ADT) almost invariably develop castration-resistant disease. The mechanism of resistance is largely based on synthesis of intratumoral androgens from adrenal precursors, requiring enzymatic action of 3β-hydroxysteroid dehydrogenase/Δ5→4 isomerase 1 (3β-HSD1), encoded by HSD3B1. A nucleotide polymorphism (1245A>C) in HSD3B1 results in a protein variant with increased steady-state levels and subsequently increased androgen synthesis from extragonadal precursors. Multiple clinical studies have shown that patients with the variant allele have significantly worse outcomes after ADT than those without, indicating that HSD3B1 variant status is a predictive biomarker of shortened ADT response. In addition, inheritance of the HSD3B1 variant is associated with extended responses to 17α-hydroxylase/17,20-lyase (CYP17A1) inhibition with a nonsteroidal agent, adding to evidence of increased tumour dependence on extragonadal androgens in patients who inherited the HSD3B1 variant. However, steroidal drugs with a 3β-hydroxyl, Δ5-structure, such as abiraterone, are also metabolized by 3β-HSD1, and 5α-abiraterone, a downstream metabolite, has been shown to activate the androgen receptor, potentially driving cancer progression. These data indicate a potential requirement to modify the treatment framework of patients harbouring variant HSD3B1.

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Affiliations

  1. Daniel Hettel is at the Lerner College of Medicine, Education Institute, and the Department of Cancer Biology, Lerner Research Institute, 9500 Euclid Avenue, Cleveland Clinic, Cleveland, Ohio 44195, USA.

    • Daniel Hettel
  2. Nima Sharifi is at the Lerner College of Medicine, Education Institute, the Department of Cancer Biology, Lerner Research Institute, the Department of Urology, Glickman Urological and Kidney Institute, and the Department of Haematology and Oncology, Taussig Cancer Institute, 9500 Euclid Avenue, Cleveland Clinic, Cleveland, Ohio 44195, USA.

    • Nima Sharifi

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Contributions

Both authors researched data for the article, made substantial contributions to discussion of its content, wrote, and reviewed and/or edited the manuscript before submission.

Competing interests

A patent application has been filed by the Cleveland Clinic for a method of steroid-dependent disease treatment based on HSD3B1. N.S. is listed as a co-inventor on this patent application.

Corresponding author

Correspondence to Nima Sharifi.

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DOI

https://doi.org/10.1038/nrurol.2017.201