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  • Review Article
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Alternative splicing in prostate cancer

Nature Reviews Clinical Oncology volume 15, pages 663–675 (2018)Cite this article

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Abstract

Androgen receptor (AR) splice variants (AR-Vs) have been implicated in the development and progression of metastatic prostate cancer. AR-Vs are truncated isoforms of the AR, a subset of which lack a ligand-binding domain and remain constitutively active in the absence of circulating androgens, thus promoting cancer cell proliferation. Consequently, AR-Vs have been proposed to contribute not only to resistance to anti-androgen therapies but also to resistance to radiotherapy in patients receiving combination therapy by promoting DNA repair. AR-Vs, such as AR-V7, have been associated with unfavourable clinical outcomes in patients; however, attempts to specifically inhibit or prevent the formation of AR-Vs have, to date, been unsuccessful. Thus, novel therapeutic strategies are desperately needed to address the oncogenic effects of AR-Vs, which can drive lethal forms of prostate cancer. Disruption of alternative splicing through modulation of the spliceosome is one such potential therapeutic avenue; however, our understanding of the biology of the spliceosome and how it contributes to prostate cancer remains incomplete, as reflected in the dearth of spliceosome-targeted therapeutic agents. In this Review, the authors outline the current understanding of the role of the spliceosome in the progression of prostate cancer and explore the therapeutic utility of manipulating alternative splicing to improve patient care.

Key points

  • Persistent androgen receptor (AR) signalling is fundamental for the development of treatment resistance in prostate cancer and for its progression to lethal castration-resistant prostate cancer (CRPC).

  • Truncated AR splice variants that lack the AR ligand-binding domain (LBD) and remain constitutively active in the absence of androgen ligands are a biologically credible mechanism of treatment resistance in CRPC. These splice variants occur through the process of alternative splicing, which is regulated by the spliceosome.

  • AR splice variant 7 (AR-V7) is the most widely studied AR splice variant and has been associated with both an increased risk of biochemical relapse and inferior overall survival outcomes.

  • Efforts to directly target AR splice variants have proved challenging owing to the loss of the LBD (the target of the currently approved anti-androgen therapies) and the intrinsically disordered nature of the AR amino-terminal domain.

  • Targeting spliceosomal activity to inhibit the generation of AR splice variants represents an attractive alternative therapeutic strategy; however, the complexity of the spliceosome, and a lack of understanding of its biology, has resulted in a paucity of such agents being developed.

  • Further research is urgently required to improve understanding of the splicing abnormalities that contribute to the progression of CRPC, as well as the consequences of inhibiting these factors, before the true utility of these therapies can be realized.

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Fig. 1: AR splice variants.
Fig. 2: Summary of constitutive and alternative splicing events.
Fig. 3: Mechanisms through which the spliceosome contributes to tumorigenesis and disease progression in prostate cancer.

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Acknowledgements

A.P. gratefully acknowledges research funding from Cancer Research UK and the Wellcome Trust. A.S. gratefully acknowledges research funding from the Academy of Medical Sciences, the Medical Research Council, and Prostate Cancer UK. G.V.R. gratefully acknowledges research funding from the US Department of Defense. J.L. gratefully acknowledges research funding from the US Department of Defense Prostate Cancer Research Program (grant W81XWH-15-2-0050) and the US National Institutes of Health (NIH) (grant R01 CA185297). S.R.P. gratefully acknowledges research funding from the Lopker Family Foundation, the National Cancer Institute Center for Strategic Scientific Initiatives (P01CA163227 and P50CA097186), the Prostate Cancer Foundation, the US Department of Defense, Medical Research and Material Command (W81XWH-12-PCRP-TIA and W81XWH-15-2-0052), and the US Department of Veterans Affairs (5I01BX003324). J.S.d.B. gratefully acknowledges research funding from Cancer Research UK, the Movember Foundation, the Prostate Cancer Foundation, Prostate Cancer UK, Stand Up To Cancer, the UK Department of Health through an Experimental Cancer Medicine Centre grant, and the US Department of Defense.

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Nature Reviews Clinical Oncology thanks A. Azad, O. Caffo, and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. The Institute for Cancer Research, London, UK

    Alec Paschalis, Adam Sharp, Jonathan C. Welti, Antje Neeb & Johann. S. de Bono

  2. The Royal Marsden NHS Foundation Trust, London, UK

    Alec Paschalis, Adam Sharp & Johann. S. de Bono

  3. Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Ganesh V. Raj

  4. Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Ganesh V. Raj

  5. Department of Urology, Johns Hopkins University, Baltimore, MD, USA

    Jun Luo

  6. Department of Medicine, University of Washington School of Medicine and VAPSHCS-GRECC, Seattle, WA, USA

    Stephen R. Plymate

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All authors made a substantial contribution to all aspects of the preparation of this manuscript.

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Competing interests

A.P., A.S., J.C.W., A.N., and J.S.d.B. are employees of The Institute of Cancer Research, a not-for-profit research organization and independent college of The University of London, which has a commercial interest in abiraterone. A.P., A.S., J.C.W., A.N., and J.S.d.-B. have no personal financial interests in abiraterone. G.V.R. has acted as a consultant of Astellas, Bayer, Pfizer, and Sanofi; receives research funding from Bayer; and has ownership interest in C-diagnostics EtiraRx and GaudiumRx. J.L. has served as a paid consultant and/or adviser of Janssen, Sanofi, and Sun Pharma; has received research funding from Astellas, Constellation, Gilead, Orion, and Sanofi; and is the lead inventor of a technology that has been licensed to A&G, Qiagen, and Tokai. J.S.d.B. has served as an advisory board member for Astellas, AstraZeneca, Bayer, Genentech, Genmab, GlaxoSmithKline, Janssen, Medivation, Merck MSD, Menarini, Orion Pharma, Pfizer, Sanofi–Aventis, and Serono. S.R.P. declares no competing interests.

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Paschalis, A., Sharp, A., Welti, J.C. et al. Alternative splicing in prostate cancer. Nat Rev Clin Oncol 15, 663–675 (2018). https://doi.org/10.1038/s41571-018-0085-0

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