[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-381337-105":59,"doc-detail-381337-en":131},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":124,"head_meta":126,"extra_data":128,"updated_unix":130},105,"en","lineage-plasticity-and-treatment-resistance-in-prostate-cancer-the-intersection-of-genetics-epigenetics-and-evolution","Lineage plasticity and treatment resistance in prostate cancer - the intersection of genetics, epigenetics, and evolution","","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.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/lineage-plasticity-and-treatment-resistance-in-prostate-cancer-the-intersection-of-genetics-epigenetics-and-evolution/381337/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/lineage-plasticity-and-treatment-resistance-in-prostate-cancer-the-intersection-of-genetics-epigenetics-and-evolution/381337.png","ImageObject",300,407,{"name":92,"@type":93},"WPS_1786070896","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",14,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"Why does neuroendocrine prostate cancer develop during treatment?","Question",{"text":113,"@type":114},"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.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"Which genetic events are highlighted as drivers of NEPC differentiation?",{"text":118,"@type":114},"Loss of RB1, TP53, and PTEN expression and amplification of MYCN and AURKA are presented as key drivers for NEPC differentiation.",{"name":120,"@type":111,"acceptedAnswer":121},"How do epigenetic mechanisms contribute to treatment resistance and radioresistance?",{"text":122,"@type":114},"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.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},381337,1790625386,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146},549768072016,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","TYPE Review  \nPUBLISHED 30 June 2023  \nDOI 10.3389/fendo.2023.1191311  \nOPEN ACCESS  \nEDITED BY  \nCarlos Pe´ rez-Plasencia,  \nNational Autonomous University of Mexico, Mexico  \nREVIEWED BY  \nMauricio Rodriguez-Dorantes, National Institute of Genomic Medicine (INMEGEN), Mexico  \nSusan Kasper,  \nUniversity of Cincinnati, United States  \n*CORRESPONDENCE Jarrell Imamura  \n [imamurj2@ccf.org](imamurj2@ccf.org)[ ](imamurj2@ccf.org)Shinjini Ganguly  \n [ganguls@ccf.org](ganguls@ccf.org)  \nRECEIVED 21 March 2023  \nACCEPTED 12 June 2023  \nPUBLISHED 30 June 2023  \nCITATION  \nImamura 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.  \nFront. Endocrinol. 14:1191311 .  \ndoi: 10.3389/fendo.2023.1191311  \nCOPYRIGHT  \n© 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.  \nLineage plasticity and treatment resistance in prostate cancer: the intersection of genetics, epigenetics, and evolution  \nJarrell 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  \n1Taussig 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  \nAndrogen 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.  \nKEYWORDS  \nneuroendocrine prostate cancer, lineage plasticity, epigenetic dysregulation, hormone therapy resistance, radioresistance  \nFrontiers in Endocrinology 01 [frontiersin.org](frontiersin.org)  \n1 Introduction  \nIn American men, prostate cancer (PCa) is among the most common malignancies and is projected to become the second leading cause of cancer rel","cbCaitg1HRrcAKvi","https://ap.wps.com/l/cbCaitg1HRrcAKvi","pdf",1218474,15,"English","# Introduction\n## Prostate cancer, CRPC, and NEPC\n## Lineage plasticity and therapy resistance\n## AR dependence and AR-targeted treatments","[{\"question\":\"Why does neuroendocrine prostate cancer develop during treatment?\",\"answer\":\"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.\"},{\"question\":\"Which genetic events are highlighted as drivers of NEPC differentiation?\",\"answer\":\"Loss of RB1, TP53, and PTEN expression and amplification of MYCN and AURKA are presented as key drivers for NEPC differentiation.\"},{\"question\":\"How do epigenetic mechanisms contribute to treatment resistance and radioresistance?\",\"answer\":\"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.\"}]","Lineage plasticity and treatment resistance in prostate cancer - the intersection of genetics, epigenetics, and evolution | PDF",1790244880,38]