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

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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OTHERS THE NEUROENDOCRINE TRANSITION IN PROSTATE CANCER IS DYNAMIC AND DEPENDENT ON ASCL1 Article Open access 11 October 2024 DPYSL5 IS HIGHLY EXPRESSED IN TREATMENT-INDUCED NEUROENDOCRINE

PROSTATE CANCER AND PROMOTES LINEAGE PLASTICITY VIA EZH2/PRC2 Article Open access 18 January 2024 MOLECULAR EVENTS IN NEUROENDOCRINE PROSTATE CANCER DEVELOPMENT Article 21 July 2021

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references 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). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Vancouver Prostate Centre, 2660 Oak Street, Vancouver, BC, Canada

Alastair H. Davies & Amina Zoubeidi * Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, 2775 Laurel Street, Vancouver, BC, Canada Alastair H. Davies 

& Amina Zoubeidi * Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, 413 East 69th Street, New York, NY, USA Himisha Beltran Authors * Alastair

H. Davies View author publications You can also search for this author inPubMed Google Scholar * Himisha Beltran View author publications You can also search for this author inPubMed Google

Scholar * Amina Zoubeidi View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS 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. CORRESPONDING AUTHOR Correspondence to

Amina Zoubeidi. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR FIG. 2

POWERPOINT SLIDE FOR FIG. 3 POWERPOINT SLIDE FOR FIG. 4 POWERPOINT SLIDE FOR TABLE 1 POWERPOINT SLIDE FOR TABLE 2 RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS

ARTICLE Davies, A., Beltran, H. & Zoubeidi, A. Cellular plasticity and the neuroendocrine phenotype in prostate cancer. _Nat Rev Urol_ 15, 271–286 (2018).

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