Lineage plasticity and treatment resistance in prostate cancer - the intersection of genetics, epigenetics, and evolution

Sep 24, 2026

Androgen deprivation therapy is central for advanced prostate cancer, yet castrate-resistant prostate cancer (CRPC) drives most prostate cancer mortality. Reviews highlight that CRPC can evolve beyond androgen receptor (AR) dependence through genetic, epigenetic, and hormonal changes that increase cellular plasticity, producing AR-indifferent disease and neuroendocrine prostate cancer (NEPC) after second-generation antiandrogens. Key drivers include loss of RB1, TP53, and PTEN, plus MYCN and AURKA amplification, while DNA methylation and histone methylation remodel lineage commitment; EZH2 is implicated. Multiple AR-dependent resistance routes and epigenetically mediated radioresistance support emerging combination therapies.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Introduction

Prostate cancer, CRPC, and NEPC

Lineage plasticity and therapy resistance

AR dependence and AR-targeted treatments

TYPE Review PUBLISHED 30 June 2023 DOI 10.3389/fendo.2023.1191311 OPEN ACCESS EDITED BY Carlos Pe´ rez-Plasencia, National Autonomous University of Mexico, Mexico REVIEWED BY Mauricio Rodriguez-Dorantes, National Institute of Genomic Medicine (INMEGEN), Mexico Susan Kasper, University of Cincinnati, United States *CORRESPONDENCE Jarrell Imamura [imamurj2@ccf.org](imamurj2@ccf.org)[ ](imamurj2@ccf.org)Shinjini Ganguly [ganguls@ccf.org](ganguls@ccf.org) RECEIVED 21 March 2023 ACCEPTED 12 June 2023 PUBLISHED 30 June 2023 CITATION Imamura J, Ganguly S, Muskara A, Liao RS, Nguyen JK, Weight C, Wee CE, Gupta Sand Mian OY (2023) Lineage plasticity and treatment resistance in prostate cancer: the intersection of genetics, epigenetics, and evolution. Front. Endocrinol. 14:1191311 . doi: 10.3389/fendo.2023.1191311 COPYRIGHT © 2023 Imamura, Ganguly, Muskara, Liao, Nguyen, Weight, Wee, Gupta and Mian. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Lineage plasticity and treatment resistance in prostate cancer: the intersection of genetics, epigenetics, and evolution Jarrell Imamura 1*, Shinjini Ganguly 1*, Andrew Muskara 1, Ross S. Liao 2, Jane K. Nguyen 2,3, Christopher Weight 2, Christopher E. Wee 1, Shilpa Gupta 1 and Omar Y. Mian 1 1Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, United States, 2Glickman Urologic Institute, Cleveland Clinic, Cleveland, OH, United States, 3 Department of Pathology, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, United States Androgen deprivation therapy is a cornerstone of treatment for advanced prostate cancer, and the development of castrate-resistant prostate cancer (CRPC) is the primary cause of prostate cancer-related mortality. While CRPC typically develops through a gain in androgen receptor (AR) signaling, a subset of CRPC will lose reliance on the AR. This process involves genetic, epigenetic, and hormonal changes that promote cellular plasticity, leading to AR-indifferent disease, with neuroendocrine prostate cancer (NEPC) being the quintessential example. NEPC is enriched following treatment with second-generation antiandrogens and exhibits resistance to endocrine therapy. Loss of RB1, TP53, and PTEN expression and MYCN andAURKA ampliﬁcation appear to be key drivers for NEPC differentiation. Epigenetic modiﬁcations also play an important role in the transition to a neuroendocrine phenotype. DNA methylation of speciﬁc gene promoters can regulate lineage commitment and differentiation. Histone methylation can suppress AR expression and promote neuroendocrinespeciﬁc gene expression. Emerging data suggest that EZH2 is a key regulator of this epigenetic rewiring. Several mechanisms drive AR-dependent castration resistance, notably AR splice variant expression, expression of the adrenalpermissive 3bHSD1 allele, and glucocorticoid receptor expression. Aberrant epigenetic regulation also promotes radioresistance by altering the expression of DNA repair-and cell cycle-related genes. Novel therapies are currently being developed to target these diverse genetic, epigenetic, and hormonal mechanisms promoting lineage plasticity-driven NEPC. KEYWORDS neuroendocrine prostate cancer, lineage plasticity, epigenetic dysregulation, hormone therapy resistance, radioresistance Frontiers in Endocrinology 01 [frontiersin.org](frontiersin.org) 1 Introduction In American men, prostate cancer (PCa) is among the most common malignancies and is projected to become the second leading cause of cancer rel

FAQs

Why does neuroendocrine prostate cancer develop during treatment?

The review describes NEPC as arising from lineage plasticity, including transdifferentiation of adenocarcinoma toward a neuroendocrine (NE) lineage in response to therapy and other environmental stimuli.

Which genetic events are highlighted as drivers of NEPC differentiation?

Loss of RB1, TP53, and PTEN expression and amplification of MYCN and AURKA are presented as key drivers for NEPC differentiation.

How do epigenetic mechanisms contribute to treatment resistance and radioresistance?

Epigenetic modifications such as DNA methylation and histone methylation can regulate lineage commitment and suppress AR expression while promoting neuroendocrine gene programs; aberrant epigenetic regulation also promotes radioresistance by altering DNA repair and cell cycle-related gene expression.

Sep 24, 2026

Uploaded by WPS_1786070896