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Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids

Prostate Cancer and Prostatic Diseases volume 26, pages 293–301 (2023)Cite this article

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Abstract

Background

Androgen receptor (AR) ligand-binding domain (LBD) mutations occur in ~20% of all castration-resistant prostate cancer (CRPC) patients. These mutations confer ligand promiscuity, but the affinity for many steroid hormone pathway intermediates is unknown. In this study, we investigated the stimulation of clinically relevant AR-LBD mutants by endogenous and exogenous steroid hormones present in CRPC patients to unravel their potential contribution to AR pathway reactivation.

Methods

A meta-analysis of studies reporting untargeted analysis of AR mutants was performed to identify clinically relevant AR-LBD mutations. Using luciferase reporter and quantitative fluorescent microscopy, these AR mutants were screened for sensitivity for various endogenous steroids and synthetic glucocorticoids used in the treatment of CRPC.

Results

The meta-analysis revealed that ARL702H (3.4%), ARH875Y (4.9%), and ART878A (4.4%) were the most prevalent AR-LBD mutations across 1614 CRPC patients from 21 unique studies. Testosterone (EC50: 0.22 nmol/L) and 11-ketotestosterone (11KT, EC50: 0.74 nmol/L) displayed subnanomolar affinity for ARWT. The p.H875Y mutation selectively increased sensitivity of the AR for 11KT (EC50: 0.15 nmol/L, p < 0.05 vs ARWT), whereas p.L702H decreased sensitivity for 11KT by almost 50-fold. While cortisol and prednisolone both stimulate ARL702H, dexamethasone importantly does not.

Conclusion

Both testosterone and 11KT effectively contribute to ARWT activation, while selective sensitization positions 11KT as a more prominent activator of ARH875Y. Dexamethasone may be a suitable alternative to prednisolone and should be explored in patients bearing the ARL702H.

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Fig. 1: In vitro activation of wild-type and ligand-binding domain mutant androgen receptors by canonical and 11-oxygenated androgens.
Fig. 2: AR nuclear fraction in response to androgens and 11-oxygenated androgens.
Fig. 3: Activation of wild-type and mutant androgen receptor by exogenous glucocorticoids commonly used in prostate cancer patients.
Fig. 4: Relation between AR-LBD mutant ligand sensitivity and circulating steroid concentrations in CRPC patients.

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Data availability

The studies included meta-analysis were retrieved from PubMed and are publicly available. The data sets generated during the present study are available from the corresponding author upon reasonable request.

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Funding

This study was funded by the Daniel den Hoed Foundation (investigator award to JH and funding support for the CTSF/Opera Phenix system) and by royalties from AMH assays paid to the Visser lab (JAV).

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Author notes

  1. These authors contributed equally: Jenny A. Visser, Johannes Hofland.

Authors and Affiliations

  1. Department of Internal Medicine, Section of Endocrinology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands

    Gido Snaterse, Rosinda Mies, Jenny A. Visser & Johannes Hofland

  2. Department of Urology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

    Wytske M. van Weerden

  3. Cancer Treatment Screening Facility, Department of Neurology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

    Pim J. French

  4. Section of Molecular Metabolism and Nutrition, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    Johan W. Jonker

  5. Department of Pathology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

    Adriaan B. Houtsmuller & Martin E. van Royen

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Contributions

Statement Conceptualization GS, MEvR, JAV, JH Methodology WMvW PJF, JWJ, ABH MEvR Validation GS, RM, MEvR Formal analysis GS Investigation GS, RM, MEvR Resources WMvR, PJF, JWJ, MEvR, JAV Writing original draft GS Writing—review & editing All authors Visualization GS Supervision JAV, JH Project administration JAV, JH Funding acquisition PJF, JAV, JH.

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Correspondence to Johannes Hofland.

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Snaterse, G., Mies, R., van Weerden, W.M. et al. Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids. Prostate Cancer Prostatic Dis 26, 293–301 (2023). https://doi.org/10.1038/s41391-022-00491-z

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