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Cellular plasticity and the neuroendocrine phenotype in prostate cancer

Nature Reviews Urology volume 15, pages 271–286 (2018)Cite this article

Subjects

Key Points

  • Emerging experimental and clinical evidence posits that phenotypic plasticity — that is, the ability of cells to reversibly alter their lineage identity — drives resistance to next-generation androgen receptor (AR) pathway inhibitors

  • Following treatment with AR pathway inhibitors, ∼20–25% of patients with prostate cancer relapse with tumours that have shed their dependence on the AR and have neuroendocrine features; these cancers are termed neuroendocrine prostate cancer (NEPC)

  • Reprogramming to an NEPC state is linked to reactivation of developmental transcriptional programmes involving brain-specific homeobox/POU domain protein 2 (BRN2) and transcription factor SOX2, which endow prostate cancer cells with epithelial–mesenchymal plasticity and stem-like cell properties

  • NEPCs have few genomic aberrations, with the exception of MYCN amplification, TP53 mutation or deletion, and loss of RB1, suggesting that transdifferentiation is driven largely by epigenetic dysregulation and/or signals from the tumour microenvironment

  • Polycomb group protein-mediated epigenetic silencing is notably altered in NEPC, predominantly owing to overexpression of the epigenetic modifier enhancer of zeste homologue 2 (EZH2)

  • Epigenetic therapy, such as targeting EZH2, to block neuroendocrine differentiation and/or reverse the lineage switch and restore sensitivity to AR pathway inhibitors is a promising avenue to improve prostate cancer therapy

Abstract

The success of next-generation androgen receptor (AR) pathway inhibitors, such as abiraterone acetate and enzalutamide, in treating prostate cancer has been hampered by the emergence of drug resistance. This acquired drug resistance is driven, in part, by the ability of prostate cancer cells to change their phenotype to adopt AR-independent pathways for growth and survival. Around one-quarter of resistant prostate tumours comprise cells that have undergone cellular reprogramming to become AR-independent and to acquire a continuum of neuroendocrine characteristics. These highly aggressive and lethal tumours, termed neuroendocrine prostate cancer (NEPC), exhibit reactivation of developmental programmes that are associated with epithelial–mesenchymal plasticity and acquisition of stem-like cell properties. In the past few years, our understanding of the link between lineage plasticity and an emergent NEPC phenotype has considerably increased. This new knowledge can contribute to novel therapeutic modalities that are likely to improve the treatment and clinical management of aggressive prostate cancer.

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Figure 1: Emerging resistance mechanisms to next-generation androgen receptor pathway inhibitors.
Figure 2: Mechanisms of neuroendocrine differentiation in response to androgen receptor pathway inhibitors.
Figure 3: Key signalling nodes mediating cellular plasticity and neuroendocrine differentiation.
Figure 4: A progressive model of tumour cell lineage plasticity.

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Acknowledgements

A.H.D. is supported by a Prostate Cancer Foundation (PCF) Young Investigator Award, in addition to the Canadian Institutes of Health Research. H.B. is supported by the US Department of Defense, Damon Runyon Cancer Research Foundation, and PCF. Work in the laboratory of A.Z. is supported by funds from a PCF Challenge Award, Prostate Cancer Canada (grant T2013-01), and the Terry Fox Research Institute (grant F15-05505).

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Authors and Affiliations

  1. Vancouver Prostate Centre, 2660 Oak Street, Vancouver, BC, Canada

    Alastair H. Davies & Amina Zoubeidi

  2. Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, 2775 Laurel Street, Vancouver, BC, Canada

    Alastair H. Davies & Amina Zoubeidi

  3. Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, 413 East 69th Street, New York, NY, USA

    Himisha Beltran

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A.H.D. researched data for the article and wrote the manuscript. A.H.D, H.B., and A.Z. made substantial contributions to discussion of the article content and reviewed and/or edited the manuscript before submission.

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Correspondence to Amina Zoubeidi.

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Davies, A., Beltran, H. & Zoubeidi, A. Cellular plasticity and the neuroendocrine phenotype in prostate cancer. Nat Rev Urol 15, 271–286 (2018). https://doi.org/10.1038/nrurol.2018.22

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