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

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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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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