Clinical Relevance of Androgen Receptor Splice Variants in Castration-Resistant Prostate Cancer

Opinion statement

Metastatic castration-resistant prostate cancer (mCRPC) currently benefits from a wealth of treatment options, yet still remains lethal in the vast majority of patients. It is becoming increasingly understood that this disease entity continues to evolve over time, acquiring additional and diverse resistance mechanisms with each subsequent therapy used. This dynamic relationship between treatment pressure and disease resistance can be challenging for the managing clinician. The recent discovery of alternate splice variants of the androgen receptor (AR) is one potential mechanism of escape in mCRPC, and recognizing this resistance mechanism might be important for optimal treatment selection for our patients. AR-V7 appears to be the most relevant AR splice variant, and early clinical data suggest that it is a negative prognostic marker in mCRPC. Emerging evidence also suggests that detection of AR-V7 may be associated with resistance to novel hormonal therapy (abiraterone and enzalutamide) but may be compatible with sensitivity to taxane chemotherapy (docetaxel and cabazitaxel). Adding to this complexity is the observation that AR-V7 is a dynamic marker whose status may change across time and depending on selective pressures induced by different therapies. Finally, it is possible that AR-V7 may represent a therapeutic target in mCRPC if drugs can be designed that degrade or inhibit AR splice variants or block their transcriptional activity. Several such agents (including galeterone, EPI-506, and bromodomain/BET inhibitors) are now in clinical development.

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Acknowledgments

This work was partially funded by a 2012 Prostate Cancer Foundation (PCF) Young Investigator Award and the NIH grant P30 CA006973 (E.S.A.), as well as a 2015 Conquer Cancer Foundation (CCF) Young Investigator Award (B.L.M).

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Correspondence to Emmanuel S. Antonarakis MD.

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Benjamin L. Maughan declares that he has no conflict of interest.

Emmanuel S. Antonarakis has received financial support through grants from Janssen, Astellas, Sanofi U.S., Medivation, Johnson & Johnson, Aragon Pharmaceuticals, Exelixis, Genentech, Novartis, and Tokai Pharmaceuticals; has received compensation from Astellas, Sanofi U.S., Medivation, and ESSA for service as a consultant; and is a co-inventory of a technology related to AR-V7 detection that has been licensed to Tokai Phamaceuticals.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Genitourinary Cancers

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Maughan, B.L., Antonarakis, E.S. Clinical Relevance of Androgen Receptor Splice Variants in Castration-Resistant Prostate Cancer. Curr. Treat. Options in Oncol. 16, 57 (2015). https://doi.org/10.1007/s11864-015-0375-z

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Keywords

  • Castration-resistant prostate cancer
  • Androgen receptor variants
  • AR-V7
  • Resistance
  • Hormonal therapy
  • Abiraterone
  • Enzalutamide
  • Taxane