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  • Review Article
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Androgen receptor variant-driven prostate cancer II: advances in laboratory investigations

Prostate Cancer and Prostatic Diseases volume 23, pages 381–397 (2020)Cite this article

Subjects

Abstract

Background

The androgen receptor (AR) is a key prostate cancer drug target. Suppression of AR signaling mediated by the full-length AR (AR-FL) is the therapeutic goal of all existing AR-directed therapies. AR-targeting agents impart therapeutic benefit, but lead to AR aberrations that underlie disease progression and therapeutic resistance. Among the AR aberrations specific to castration-resistant prostate cancer (CRPC), AR variants (AR-Vs) have emerged as important indicators of disease progression and therapeutic resistance.

Methods

We conducted a systemic review of the literature focusing on recent laboratory studies on AR-Vs following our last review article published in 2016. Topics ranged from measurement and detection, molecular origin, regulation, genomic function, and preclinical therapeutic targeting of AR-Vs. We provide expert opinions and perspectives on these topics.

Results

Transcript sequences for 22 AR-Vs have been reported in the literature. Different AR-Vs may arise through different mechanisms, and can be regulated by splicing factors and dictated by genomic rearrangements, but a low-androgen environment is a prerequisite for generation of AR-Vs. The unique transcript structures allowed development of in situ and in-solution measurement and detection methods, including mRNA and protein detection, in both tissue and blood specimens. AR-V7 remains the main measurement target and the most extensively characterized AR-V. Although AR-V7 coexists with AR-FL, genomic functions mediated by AR-V7 do not require the presence of AR-FL. The distinct cistromes and transcriptional programs directed by AR-V7 and their coregulators are consistent with genomic features of progressive disease in a low-androgen environment. Preclinical development of AR-V-directed agents currently focuses on suppression of mRNA expression and protein degradation as well as targeting of the amino-terminal domain.

Conclusions

Current literature continues to support AR-Vs as biomarkers and therapeutic targets in prostate cancer. Laboratory investigations reveal both challenges and opportunities in targeting AR-Vs to overcome resistance to current AR-directed therapies.

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Fig. 1: Decoding the androgen receptor splice variant transcripts.
Fig. 2: Regulatory mechanisms involved in AR-V expression.
Fig. 3: Novel preclinical agents that suppress AR/AR-Vs by regulating gene expression, degradation, AR transcriptional activity, and downstream signaling.

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Acknowledgements

ESA has received funding from the Prostate Cancer Foundation, the Patrick C. Walsh Fund, and NIH grants R01 CA185297 and P30 CA006973. AJA has received funding from a Prostate Cancer Foundation and Movember Global Treatment Sciences Challenge Award and the NIH under a P30 CA014236 and 1R01CA233585-01 grant. JL is currently funded by a Prostate Cancer Foundation grant, NIH grant R01 CA185297, and US Department of Defense Prostate Cancer Research Program grant W81XWH-19-1-0686.

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  1. These authors contributed equally: Emmanuel S. Antonarakis, Andrew J. Armstrong, Jun Luo

Authors and Affiliations

  1. Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Changxue Lu, Emmanuel S. Antonarakis & Jun Luo

  2. Departments of Medicine, Surgery, and Pharmacology and Cancer Biology, Divisions of Medical Oncology and Urology, Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, NC, USA

    Landon C. Brown & Andrew J. Armstrong

  3. Departments of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Emmanuel S. Antonarakis & Jun Luo

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ESA has served as a paid consultant/advisor for Janssen, Pfizer, Sanofi, Dendreon, Essa, Merck, Bristol-Myers Squibb, AstraZeneca, Clovis, Eli Lilly, and Amgen; has received research funding to his institution from Janssen, Johnson & Johnson, Sanofi, Dendreon, Genentech, Novartis, Tokai, Merck, Bristol-Myers Squibb, AstraZeneca, and Constellation; and is a co-inventor of an AR-V7 biomarker technology that has been licensed to Qiagen. AJA has served as a paid consultant for AstraZeneca, Merck, Dendreon, Janssen, Clovis, Bayer, and Medivation/Astellas; is on the speaker’s bureau for Bayer and Dendreon; and receives research funding to his institution from Janssen, Medivation/Astellas, Sanofi-Aventis, Active Biotech, Bayer, Dendreon, Merck, AstraZeneca, Genentech/Roche, BMS, Constellation, Novartis, and Pfizer. JL has served as a paid consultant/advisor for Sun Pharma, Janssen, Tolero, and Sanofi; has received research funding to his institution from Orion, Mirati, Astellas, Sanofi, Constellation, Calibr, Pandomedx, and Gilead; and is a co-inventor of a technology that has been licensed to Tokai, Qiagen, and A&G. CL is a co-inventor of a technology that has been licensed to Tokai and Qiagen.

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Lu, C., Brown, L.C., Antonarakis, E.S. et al. Androgen receptor variant-driven prostate cancer II: advances in laboratory investigations. Prostate Cancer Prostatic Dis 23, 381–397 (2020). https://doi.org/10.1038/s41391-020-0217-3

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