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Androgen receptor variant-driven prostate cancer: clinical implications and therapeutic targeting

Prostate Cancer and Prostatic Diseases volume 19, pages 231–241 (2016)Cite this article

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Abstract

While there are myriad mechanisms of primary and acquired resistance to conventional and next-generation hormonal therapies in prostate cancer, the potential role of androgen receptor splice variants (AR-Vs) has recently gained momentum. AR-Vs are abnormally truncated isoforms of the androgen receptor (AR) protein that lack the COOH-terminal domain but retain the NH2-terminal domain and DNA-binding domain and are thus constitutively active even in the absence of ligands. Although multiple preclinical studies have previously implicated AR-Vs in the development of castration resistance as well as resistance to abiraterone and enzalutamide, recent technological advances have made it possible to reliably detect and quantify AR-Vs from human clinical tumor specimens including blood samples. Initial clinical studies have now shown that certain AR-Vs, in particular AR-V7, may be associated with resistance to abiraterone and enzalutamide but not taxane chemotherapies when detected in circulating tumor cells. Efforts are now underway to clinically validate AR-V7 as a relevant treatment-selection biomarker in the context of other key genomic aberrations in men with metastatic castration-resistant prostate cancer. Additional efforts are underway to therapeutically target both AR and AR-Vs either directly or indirectly. Whether AR-Vs represent drivers of castration-resistant prostate cancer, or whether they are simply passenger events associated with aggressive disease or clonal heterogeneity, will ultimately be answered only through these types of clinical trials.

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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. SMD is currently funded by a Movember/Prostate Cancer Foundation Challenge Award, American Cancer Society Research Scholar Grant RSG-12-031-01-TBE, NIH grant R01 CA174777, US Department of Defense Prostate Cancer Research Program grants W81XWH-12-2-0093, W81XWH-13-1-0518, W81XWH-15-1-0633, and W81XWH-15-1-0501, and a grant from the Minnesota Partnership for Biotechnology and Medical Genomics. JL is currently funded by a Prostate Cancer Foundation grant, NIH grant R01 CA185297, and US Department of Defense Prostate Cancer Research Program grants W81XWH-13-2-0093 and W81XWH-15-2-0050.

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Author notes

  1. E S Antonarakis and A J Armstrong: Co-first authors.

  2. S M Dehm and J Luo: Co-senior authors.

Authors and Affiliations

  1. Departments of Oncology and Urology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA

    E S Antonarakis

  2. Departments of Medicine, Divisions of Medical Oncology and Urology, Surgery, and Pharmacology and Cancer Biology, Duke Cancer Institute, Durham, NC, USA

    A J Armstrong

  3. Masonic Cancer Center and Departments of Laboratory Medicine and Pathology and Urology, University of Minnesota, Minneapolis, MN, USA

    S M Dehm

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

    J Luo

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  1. E S Antonarakis
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  2. A J Armstrong
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  4. J Luo
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Corresponding author

Correspondence to E S Antonarakis.

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Competing interests

ESA has served as a paid consultant/advisor for Janssen, Astellas, Sanofi, Dendreon, Essa, and Medivation; has received research funding to his institution from Janssen, Johnson & Johnson, Sanofi, Dendreon, Exelixis, Genentech, Novartis and Tokai; and is a co-inventor of a technology that has been licensed to Tokai. AJA has served as a paid consultant for Sanofi-aventis, Dendreon, Janssen, Eisai, Bayer and Medivation/Astellas; is on the speaker’s bureau for Sanofi-aventis and Dendreon; and receives research funding to his institution from Janssen, Medivation/Astellas, Sanofi-aventis, Active Biotech, Bayer, Dendreon, Novartis and Pfizer. SMD has served as a paid consultant/advisor for Medivation/Astellas. JL has served as a paid consultant/advisor for Astellas, Gilead and Sanofi; has received research funding to his institution from Orion, Mirati, Astellas, Sanofi and Gilead; and is a co-inventor of a technology that has been licensed to A&G and Tokai.

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Antonarakis, E., Armstrong, A., Dehm, S. et al. Androgen receptor variant-driven prostate cancer: clinical implications and therapeutic targeting. Prostate Cancer Prostatic Dis 19, 231–241 (2016). https://doi.org/10.1038/pcan.2016.17

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