urovestВестник урологииUrology Herald2308-6424Rostov State Medical University10.21886/2308-6424-2026-14-3-110-118urovest-1248Research ArticleКЛИНИЧЕСКИЕ НАБЛЮДЕНИЯCLINICAL CASESТерапевтически индуцированный нейроэндокринный рак предстательной железыTherapy-induced neuroendocrine prostate cancerhttps://orcid.org/0000-0001-8060-6691КорчагинМ. Л.KorchaginM. P.

Михаил Павлович Корчагин

Москва

Mikhail P. Korchagin

Moscow

mihailsun@mail.ruhttps://orcid.org/0000-0002-4626-1295ФирсовК. А.FirsovK. A.

Константин Андреевич Фирсов — канд. мед. наук 

Москва

Konstantin Andreyevich Firsov — Cand.Sc. (Med)

Moscow

leneror@yandex.ruhttps://orcid.org/0000-0002-8476-7879КрыловА. С.KrylovA. S.

Александр Сергеевич Крылов — канд. мед. наук 

Москва

Alexander Sergeyevich Krylov — Cand.Sc. (Med)

Moscow

a.s.krylov@ronc.ruhttps://orcid.org/0000-0001-7748-9527МатвеевВ. Б.MatveevV. B.

Всеволод Борисович Матвеев — д-р мед. наук, профессор, акад. РАН 

Москва

Vsevolod B. Matveev — Dr.Sc.(Med), Full Prof., Acad. the RAS

Moscow

vsevolodmatveev@mail.ruНациональный медицинский исследовательский центр онкологии им. Н.Н. БлохинаРоссияBlokhin National Medical Research Centre for OncologyRussian Federation202608082026143110118Copyright © Корчагин М.Л., Фирсов К.А., Крылов А.С., Матвеев В.Б., 20262026Корчагин М.Л., Фирсов К.А., Крылов А.С., Матвеев В.Б.Korchagin M.P., Firsov K.A., Krylov A.S., Matveev V.B.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.urovest.ru/jour/article/view/1248

Терапевтически индуцированный нейроэндокринный рак предстательной железы (т-НЭРПЖ) относится к редким агрессивным формам заболевания, в основе которой заложен адаптивный ответ опухоли на стандартную андроген-депривационную терапию (АДТ). Несмотря на низкую частоту первичной диагностики, на долю т-НЭРПЖ, согласно данным крупных международных исследований, приходится до 30% случаев прогрессирования рака предстательной железы (РПЖ). Однако даже с учётом значительного роста числа публикаций в последние годы многие вопросы, касающиеся диагностики и лечения т-НЭРПЖ, остаются дискуссионными и требуют подтверждения в рамках крупных исследований. В данной статье представлен клинический случай т-НЭРПЖ, а также обобщены современные данные, посвящённые молекулярно-генетическим механизмам и ключевым сигнальным путям, лежащим в основе нейроэндокринной дифференцировки. Целью публикации служит расширение доказательной базы и углубление понимания клинических проявлений, диагностики и терапевтических стратегий при этом редком заболевании.

Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a rare and aggressive form of the disease, driven by the tumor's adaptive response to standard androgen deprivation therapy (ADT). Although its primary detection rate is low, t-NEPC accounts for up to 30% of cases of progressive prostate cancer (PCa), according to large-scale international studies. However, despite a significant increase in publications in recent years, many aspects of t-NEPC diagnosis and treatment remain controversial and require validation through large-scale research. This article presents a clinical case of t-NEPC and reviews current data on the molecular-genetic mechanisms and key signaling pathways underlying neuroendocrine differentiation. The aim of this publication is to expand the evidence base and improve the understanding of the clinical manifestations, diagnostic challenges, and therapeutic strategies for this rare disease.

рак предстательной железынейроэндокринная дифференцировкакастрационно-резистентный рак предстательной железымолекулярная генетикатерапевтически индуцированный нейроэндокринный рак предстательной железыандроген-депривационная терапияаденокарцинома предстательной железыprostate cancerneuroendocrine differentiationcastration-resistant prostate cancermolecular geneticstreatment-induced NEPCandrogen deprivation therapyprostate adenocarcinomaReferencesРretl K. Zur Frage der Endokrinie der menschlichen vorsteherdrüse. Virchows Arch. path Anat. 1944;312:392–404. (In German). DOI: 10.1007/BF02655955Рretl K. Zur Frage der Endokrinie der menschlichen vorsteherdrüse. Virchows Arch. path Anat. 1944;312:392–404. (In German). DOI: 10.1007/BF02655955Kazzaz BA. Argentaffin and argyrophil cells in the prostate. J Pathol. 1974;112(3):189-193. DOI: 10.1002/path.1711120310Kazzaz BA. Argentaffin and argyrophil cells in the prostate. J Pathol. 1974;112(3):189-193. DOI: 10.1002/path.1711120310Ковченко Г.А., Сивков А.В., Каприн А.Д. Роль определения хромогранина А в лечении больных кастрационно-резистентным раком предстательной железы. Экспериментальная и клиническая урология. 2024;17(1):75-85. DOI: 10.29188/2222-8543-2024-17-1-75-85Kovchenko G.A., Sivkov A.V., Kaprin A.D. The role of chromogranin A determination in the treatment of patients with castration-resistant prostate cancer. Experimental and Clinical Urology. 2024;17(1):75-85. (In Russian). DOI: 10.29188/2222-8543-2024-17-1-75-85Sciarra A, Mariotti G, Gentile V, Voria G, Pastore A, Monti S, Di Silverio F. Neuroendocrine differentiation in human prostate tissue: is it detectable and treatable? BJU Int. 2003;91(5):438-445. DOI: 10.1046/j.1464-410x.2003.03066.xSciarra A, Mariotti G, Gentile V, Voria G, Pastore A, Monti S, Di Silverio F. Neuroendocrine differentiation in human prostate tissue: is it detectable and treatable? BJU Int. 2003;91(5):438-445. DOI: 10.1046/j.1464-410x.2003.03066.xFine SW. Neuroendocrine tumors of the prostate. Mod Pathol. 2018;31(S1):S122-132. DOI: 10.1038/modpathol.2017.164Fine SW. Neuroendocrine tumors of the prostate. Mod Pathol. 2018;31(S1):S122-132. DOI: 10.1038/modpathol.2017.164Weaver MG, Abdul-Karim FW, Srigley J, Bostwick DG, Ro JY, Ayala AG. Paneth cell-like change of the prostate gland. A histological, immunohistochemical, and electron microscopic study. Am J Surg Pathol. 1992;16(1):62-68. DOI: 10.1097/00000478-199201000-00009Weaver MG, Abdul-Karim FW, Srigley J, Bostwick DG, Ro JY, Ayala AG. Paneth cell-like change of the prostate gland. A histological, immunohistochemical, and electron microscopic study. Am J Surg Pathol. 1992;16(1):62-68. DOI: 10.1097/00000478-199201000-00009di Sant’Agnese PA, De Mesy Jensen KL. Endocrine-paracrine cells of the prostate and prostatic urethra: an ultrastructural study. Hum Pathol. 1984;15(11):1034-1041. DOI: 10.1016/s0046-8177(84)80246-4di Sant’Agnese PA, De Mesy Jensen KL. Endocrine-paracrine cells of the prostate and prostatic urethra: an ultrastructural study. Hum Pathol. 1984;15(11):1034-1041. DOI: 10.1016/s0046-8177(84)80246-4So JS, Gordetsky J, Epstein JI. Variant of prostatic adenocarcinoma with Paneth cell-like neuroendocrine differentiation readily misdiagnosed as Gleason pattern 5. Hum Pathol. 2014;45(12):2388-2393. DOI: 10.1016/j.humpath.2014.08.004So JS, Gordetsky J, Epstein JI. Variant of prostatic adenocarcinoma with Paneth cell-like neuroendocrine differentiation readily misdiagnosed as Gleason pattern 5. Hum Pathol. 2014;45(12):2388-2393. DOI: 10.1016/j.humpath.2014.08.004Patel GK, Chugh N, Tripathi M. Neuroendocrine Differentiation of Prostate Cancer-An Intriguing Example of Tumor Evolution at Play. Cancers (Basel). 2019;11(10):1405. DOI: 10.3390/cancers11101405Patel GK, Chugh N, Tripathi M. Neuroendocrine Differentiation of Prostate Cancer-An Intriguing Example of Tumor Evolution at Play. Cancers (Basel). 2019;11(10):1405. DOI: 10.3390/cancers11101405Abrahamsson PA. Neuroendocrine cells in tumour growth of the prostate. Endocr Relat Cancer. 1999;6(4):503-519. DOI: 10.1677/erc.0.0060503Abrahamsson PA. Neuroendocrine cells in tumour growth of the prostate. Endocr Relat Cancer. 1999;6(4):503-519. DOI: 10.1677/erc.0.0060503Mucci NR, Akdas G, Manely S, Rubin MA. Neuroendocrine expression in metastatic prostate cancer: evaluation of high throughput tissue microarrays to detect heterogeneous protein expression. Hum Pathol. 2000;31(4):406-414. Erratum in: Hum Pathol. 2000;31(6):778. DOI: 10.1053/hp.2000.7295Mucci NR, Akdas G, Manely S, Rubin MA. Neuroendocrine expression in metastatic prostate cancer: evaluation of high throughput tissue microarrays to detect heterogeneous protein expression. Hum Pathol. 2000;31(4):406-414. Erratum in: Hum Pathol. 2000;31(6):778. DOI: 10.1053/hp.2000.7295Aggarwal R, Huang J, Alumkal JJ, Zhang L, Feng FY, Thomas GV, Weinstein AS, Friedl V, Zhang C, Witte ON, Lloyd P, Gleave M, Evans CP, Youngren J, Beer TM, Rettig M, Wong CK, True L, Foye A, Playdle D, Ryan CJ, Lara P, Chi KN, Uzunangelov V, Sokolov A, Newton Y, Beltran H, Demichelis F, Rubin MA, Stuart JM, Small EJ. Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study. J Clin Oncol. 2018;36(24):2492-2503. DOI: 10.1200/JCO.2017.77.6880Aggarwal R, Huang J, Alumkal JJ, Zhang L, Feng FY, Thomas GV, Weinstein AS, Friedl V, Zhang C, Witte ON, Lloyd P, Gleave M, Evans CP, Youngren J, Beer TM, Rettig M, Wong CK, True L, Foye A, Playdle D, Ryan CJ, Lara P, Chi KN, Uzunangelov V, Sokolov A, Newton Y, Beltran H, Demichelis F, Rubin MA, Stuart JM, Small EJ. Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study. J Clin Oncol. 2018;36(24):2492-2503. DOI: 10.1200/JCO.2017.77.6880Beltran H, Tomlins S, Aparicio A, Arora V, Rickman D, Ayala G, Huang J, True L, Gleave ME, Soule H, Logothetis C, Rubin MA. Aggressive variants of castration-resistant prostate cancer. Clin Cancer Res. 2014;20(11):2846-2850. DOI: 10.1158/1078-0432.CCR-13-3309Beltran H, Tomlins S, Aparicio A, Arora V, Rickman D, Ayala G, Huang J, True L, Gleave ME, Soule H, Logothetis C, Rubin MA. Aggressive variants of castration-resistant prostate cancer. Clin Cancer Res. 2014;20(11):2846-2850. DOI: 10.1158/1078-0432.CCR-13-3309Tucci M, Zichi C, Buttigliero C, Vignani F, Scagliotti GV, Di Maio M. Enzalutamide-resistant castration-resistant prostate cancer: challenges and solutions. Onco Targets Ther. 2018;11:7353-7368. DOI: 10.2147/OTT.S153764Tucci M, Zichi C, Buttigliero C, Vignani F, Scagliotti GV, Di Maio M. Enzalutamide-resistant castration-resistant prostate cancer: challenges and solutions. Onco Targets Ther. 2018;11:7353-7368. DOI: 10.2147/OTT.S153764Vlachostergios PJ, Puca L, Beltran H. Emerging Variants of CastrationResistant Prostate Cancer. Curr Oncol Rep. 2017;19(5):32. DOI: 10.1007/s11912-017-0593-6Vlachostergios PJ, Puca L, Beltran H. Emerging Variants of CastrationResistant Prostate Cancer. Curr Oncol Rep. 2017;19(5):32. DOI: 10.1007/s11912-017-0593-6Davies AH, Beltran H, Zoubeidi A. Cellular plasticity and the neuroendocrine phenotype in prostate cancer. Nat Rev Urol. 2018;15(5):271-286. DOI: 10.1038/nrurol.2018.22Davies AH, Beltran H, Zoubeidi A. Cellular plasticity and the neuroendocrine phenotype in prostate cancer. Nat Rev Urol. 2018;15(5):271-286. DOI: 10.1038/nrurol.2018.22Li Z, Sun Y, Chen X, Squires J, Nowroozizadeh B, Liang C, Huang J. p53 Mutation Directs AURKA Overexpression via miR-25 and FBXW7 in Prostatic Small Cell Neuroendocrine Carcinoma. Mol Cancer Res. 2015;13(3):584-591. DOI: 10.1158/1541-7786.MCR-14-0277-TLi Z, Sun Y, Chen X, Squires J, Nowroozizadeh B, Liang C, Huang J. p53 Mutation Directs AURKA Overexpression via miR-25 and FBXW7 in Prostatic Small Cell Neuroendocrine Carcinoma. Mol Cancer Res. 2015;13(3):584-591. DOI: 10.1158/1541-7786.MCR-14-0277-TMcKay RR, Kwak L, Crowdis JP, Sperger JM, Zhao SG, Xie W, Werner L, Lis RT, Zhang Z, Wei XX, Lang JM, Van Allen EM, Bhatt RS, Yu EY, Nelson PS, Bubley GJ, Montgomery RB, Taplin ME. Phase II Multicenter Study of Enzalutamide in Metastatic Castration-Resistant Prostate Cancer to Identify Mechanisms Driving Resistance. Clin Cancer Res. 2021;27(13):3610-3619. DOI: 10.1158/1078-0432.CCR-20-4616McKay RR, Kwak L, Crowdis JP, Sperger JM, Zhao SG, Xie W, Werner L, Lis RT, Zhang Z, Wei XX, Lang JM, Van Allen EM, Bhatt RS, Yu EY, Nelson PS, Bubley GJ, Montgomery RB, Taplin ME. Phase II Multicenter Study of Enzalutamide in Metastatic Castration-Resistant Prostate Cancer to Identify Mechanisms Driving Resistance. Clin Cancer Res. 2021;27(13):3610-3619. DOI: 10.1158/1078-0432.CCR-20-4616Puhr M, Hoefer J, Eigentler A, Ploner C, Handle F, Schaefer G, Kroon J, Leo A, Heidegger I, Eder I, Culig Z, Van der Pluijm G, Klocker H. The Glucocorticoid Receptor Is a Key Player for Prostate Cancer Cell Survival and a Target for Improved Antiandrogen Therapy. Clin Cancer Res. 2018;24(4):927-938. DOI: 10.1158/1078-0432.CCR-17-0989Puhr M, Hoefer J, Eigentler A, Ploner C, Handle F, Schaefer G, Kroon J, Leo A, Heidegger I, Eder I, Culig Z, Van der Pluijm G, Klocker H. The Glucocorticoid Receptor Is a Key Player for Prostate Cancer Cell Survival and a Target for Improved Antiandrogen Therapy. Clin Cancer Res. 2018;24(4):927-938. DOI: 10.1158/1078-0432.CCR-17-0989Shah N, Wang P, Wongvipat J, Karthaus WR, Abida W, Armenia J, Rockowitz S, Drier Y, Bernstein BE, Long HW, Freedman ML, Arora VK, Zheng D, Sawyers CL. Regulation of the glucocorticoid receptor via a BET-dependent enhancer drives antiandrogen resistance in prostate cancer. Elife. 2017;6:e27861. DOI: 10.7554/eLife.27861Shah N, Wang P, Wongvipat J, Karthaus WR, Abida W, Armenia J, Rockowitz S, Drier Y, Bernstein BE, Long HW, Freedman ML, Arora VK, Zheng D, Sawyers CL. Regulation of the glucocorticoid receptor via a BET-dependent enhancer drives antiandrogen resistance in prostate cancer. Elife. 2017;6:e27861. DOI: 10.7554/eLife.27861Venkitaraman R, Lorente D, Murthy V, Thomas K, Parker L, Ahiabor R, Dearnaley D, Huddart R, De Bono J, Parker C. A randomised phase 2 trial of dexamethasone versus prednisolone in castration-resistant prostate cancer. Eur Urol. 2015;67(4):673-679. DOI: 10.1016/j.eururo.2014.10.004Venkitaraman R, Lorente D, Murthy V, Thomas K, Parker L, Ahiabor R, Dearnaley D, Huddart R, De Bono J, Parker C. A randomised phase 2 trial of dexamethasone versus prednisolone in castration-resistant prostate cancer. Eur Urol. 2015;67(4):673-679. DOI: 10.1016/j.eururo.2014.10.004Sang M, Hulsurkar M, Zhang X, Song H, Zheng D, Zhang Y, Li M, Xu J, Zhang S, Ittmann M, Li W. GRK3 is a direct target of CREB activation and regulates neuroendocrine differentiation of prostate cancer cells. Oncotarget. 2016;7(29):45171-45185. DOI: 10.18632/oncotarget.9359Sang M, Hulsurkar M, Zhang X, Song H, Zheng D, Zhang Y, Li M, Xu J, Zhang S, Ittmann M, Li W. GRK3 is a direct target of CREB activation and regulates neuroendocrine differentiation of prostate cancer cells. Oncotarget. 2016;7(29):45171-45185. DOI: 10.18632/oncotarget.9359Zhang Y, Zheng D, Zhou T, Song H, Hulsurkar M, Su N, Liu Y, Wang Z, Shao L, Ittmann M, Gleave M, Han H, Xu F, Liao W, Wang H, Li W. Androgen deprivation promotes neuroendocrine differentiation and angiogenesis through CREB-EZH2-TSP1 pathway in prostate cancers. Nat Commun. 2018;9(1):4080. DOI: 10.1038/s41467-018-06177-2Zhang Y, Zheng D, Zhou T, Song H, Hulsurkar M, Su N, Liu Y, Wang Z, Shao L, Ittmann M, Gleave M, Han H, Xu F, Liao W, Wang H, Li W. Androgen deprivation promotes neuroendocrine differentiation and angiogenesis through CREB-EZH2-TSP1 pathway in prostate cancers. Nat Commun. 2018;9(1):4080. DOI: 10.1038/s41467-018-06177-2Viré E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, Morey L, Van Eynde A, Bernard D, Vanderwinden JM, Bollen M, Esteller M, Di Croce L, de Launoit Y, Fuks F. The Polycomb group protein EZH2 directly controls DNA methylation. Nature. 2006;439(7078):871-874. Erratum in: Nature. 2007;446(7137):824. DOI: 10.1038/nature04431Viré E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, Morey L, Van Eynde A, Bernard D, Vanderwinden JM, Bollen M, Esteller M, Di Croce L, de Launoit Y, Fuks F. The Polycomb group protein EZH2 directly controls DNA methylation. Nature. 2006;439(7078):871-874. Erratum in: Nature. 2007;446(7137):824. DOI: 10.1038/nature04431Marignol L, Rivera-Figueroa K, Lynch T, Hollywood D. Hypoxia, notch signalling, and prostate cancer. Nat Rev Urol. 2013;10(7):405-413. DOI: 10.1038/nrurol.2013.110Marignol L, Rivera-Figueroa K, Lynch T, Hollywood D. Hypoxia, notch signalling, and prostate cancer. Nat Rev Urol. 2013;10(7):405-413. DOI: 10.1038/nrurol.2013.110Puca L, Gavyert K, Sailer V, Conteduca V, Dardenne E, Sigouros M, Isse K, Kearney M, Vosoughi A, Fernandez L, Pan H, Motanagh S, HessJ, Donoghue AJ, Sboner A, Wang Y, Dittamore R, Rickman D, Nanus DM, Tagawa ST, Elemento O, Mosquera JM, Saunders L, Beltran H. Deltalike protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer. Sci Transl Med. 2019;11(484):eaav0891. DOI: 10.1126/scitranslmed.aav0891Puca L, Gavyert K, Sailer V, Conteduca V, Dardenne E, Sigouros M, Isse K, Kearney M, Vosoughi A, Fernandez L, Pan H, Motanagh S, HessJ, Donoghue AJ, Sboner A, Wang Y, Dittamore R, Rickman D, Nanus DM, Tagawa ST, Elemento O, Mosquera JM, Saunders L, Beltran H. Deltalike protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer. Sci Transl Med. 2019;11(484):eaav0891. DOI: 10.1126/scitranslmed.aav0891Danza G, Di Serio C, Rosati F, Lonetto G, Sturli N, Kacer D, Pennella A, Ventimiglia G, Barucci R, Piscazzi A, Prudovsky I, Landriscina M, Marchionni N, Tarantini F. Notch signaling modulates hypoxia-induced neuroendocrine differentiation of human prostate cancer cells. Mol Cancer Res. 2012;10(2):230-238. DOI: 10.1158/1541-7786.MCR-11-0296Danza G, Di Serio C, Rosati F, Lonetto G, Sturli N, Kacer D, Pennella A, Ventimiglia G, Barucci R, Piscazzi A, Prudovsky I, Landriscina M, Marchionni N, Tarantini F. Notch signaling modulates hypoxia-induced neuroendocrine differentiation of human prostate cancer cells. Mol Cancer Res. 2012;10(2):230-238. DOI: 10.1158/1541-7786.MCR-11-0296Guo H, Ci X, Ahmed M, Hua JT, Soares F, Lin D, Puca L, Vosoughi A, Xue H, Li E, Su P, Chen S, Nguyen T, Liang Y, Zhang Y, Xu X, Xu J, Sheahan AV, Ba-Alawi W, Zhang S, Mahamud O, Vellanki RN, Gleave M, Bristow RG, Haibe-Kains B, Poirier JT, Rudin CM, Tsao MS, Wouters BG, Fazli L, Feng FY, Ellis L, van der Kwast T, Berlin A, Koritzinsky M, Boutros PC, Zoubeidi A, Beltran H, Wang Y, He HH. ONECUT2 is a driver of neuroendocrine prostate cancer. Nat Commun. 2019;10(1):278. DOI: 10.1038/s41467-018-08133-6Guo H, Ci X, Ahmed M, Hua JT, Soares F, Lin D, Puca L, Vosoughi A, Xue H, Li E, Su P, Chen S, Nguyen T, Liang Y, Zhang Y, Xu X, Xu J, Sheahan AV, Ba-Alawi W, Zhang S, Mahamud O, Vellanki RN, Gleave M, Bristow RG, Haibe-Kains B, Poirier JT, Rudin CM, Tsao MS, Wouters BG, Fazli L, Feng FY, Ellis L, van der Kwast T, Berlin A, Koritzinsky M, Boutros PC, Zoubeidi A, Beltran H, Wang Y, He HH. ONECUT2 is a driver of neuroendocrine prostate cancer. Nat Commun. 2019;10(1):278. DOI: 10.1038/s41467-018-08133-6McNair C, Xu K, Mandigo AC, Benelli M, Leiby B, Rodrigues D, Lindberg J, Gronberg H, Crespo M, De Laere B, Dirix L, Visakorpi T, Li F, Feng FY, de Bono J, Demichelis F, Rubin MA, Brown M, Knudsen KE. Differential impact of RB status on E2F1 reprogramming in human cancer. J Clin Invest. 2018;128(1):341-358. DOI: 10.1172/JCI93566McNair C, Xu K, Mandigo AC, Benelli M, Leiby B, Rodrigues D, Lindberg J, Gronberg H, Crespo M, De Laere B, Dirix L, Visakorpi T, Li F, Feng FY, de Bono J, Demichelis F, Rubin MA, Brown M, Knudsen KE. Differential impact of RB status on E2F1 reprogramming in human cancer. J Clin Invest. 2018;128(1):341-358. DOI: 10.1172/JCI93566Beltran H, Prandi D, Mosquera JM, Benelli M, Puca L, Cyrta J, Marotz C, Giannopoulou E, Chakravarthi BV, Varambally S, Tomlins SA, Nanus DM, Tagawa ST, Van Allen EM, Elemento O, Sboner A, Garraway LA, Rubin MA, Demichelis F. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat Med. 2016;22(3):298-305. DOI: 10.1038/nm.4045Beltran H, Prandi D, Mosquera JM, Benelli M, Puca L, Cyrta J, Marotz C, Giannopoulou E, Chakravarthi BV, Varambally S, Tomlins SA, Nanus DM, Tagawa ST, Van Allen EM, Elemento O, Sboner A, Garraway LA, Rubin MA, Demichelis F. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat Med. 2016;22(3):298-305. DOI: 10.1038/nm.4045Dardenne E, Beltran H, Benelli M, Gayvert K, Berger A, Puca L, Cyrta J, Sboner A, Noorzad Z, MacDonald T, Cheung C, Yuen KS, Gao D, Chen Y, Eilers M, Mosquera JM, Robinson BD, Elemento O, Rubin MA, Demichelis F, Rickman DS. N-Myc Induces an EZH2-Mediated Transcriptional Program Driving Neuroendocrine Prostate Cancer. Cancer Cell. 2016;30(4):563-577. DOI: 10.1016/j.ccell.2016.09.005Dardenne E, Beltran H, Benelli M, Gayvert K, Berger A, Puca L, Cyrta J, Sboner A, Noorzad Z, MacDonald T, Cheung C, Yuen KS, Gao D, Chen Y, Eilers M, Mosquera JM, Robinson BD, Elemento O, Rubin MA, Demichelis F, Rickman DS. N-Myc Induces an EZH2-Mediated Transcriptional Program Driving Neuroendocrine Prostate Cancer. Cancer Cell. 2016;30(4):563-577. DOI: 10.1016/j.ccell.2016.09.005Lee JK, Phillips JW, Smith BA, Park JW, Stoyanova T, McCaffrey EF, Baertsch R, Sokolov A, Meyerowitz JG, Mathis C, Cheng D, Stuart JM, Shokat KM, Gustafson WC, Huang J, Witte ON. N-Myc Drives Neuroendocrine Prostate Cancer Initiated from Human Prostate Epithelial Cells. Cancer Cell. 2016;29(4):536-547. DOI: 10.1016/j.ccell.2016.03.001Lee JK, Phillips JW, Smith BA, Park JW, Stoyanova T, McCaffrey EF, Baertsch R, Sokolov A, Meyerowitz JG, Mathis C, Cheng D, Stuart JM, Shokat KM, Gustafson WC, Huang J, Witte ON. N-Myc Drives Neuroendocrine Prostate Cancer Initiated from Human Prostate Epithelial Cells. Cancer Cell. 2016;29(4):536-547. DOI: 10.1016/j.ccell.2016.03.001Beltran H, Rickman DS, Park K, Chae SS, Sboner A, MacDonald TY, Wang Y, Sheikh KL, Terry S, Tagawa ST, Dhir R, Nelson JB, de la Taille A, Allory Y, Gerstein MB, Perner S, Pienta KJ, Chinnaiyan AM, Wang Y, Collins CC, Gleave ME, Demichelis F, Nanus DM, Rubin MA. Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discov. 2011;1(6):487-495. DOI: 10.1158/2159-8290.CD-11-0130Beltran H, Rickman DS, Park K, Chae SS, Sboner A, MacDonald TY, Wang Y, Sheikh KL, Terry S, Tagawa ST, Dhir R, Nelson JB, de la Taille A, Allory Y, Gerstein MB, Perner S, Pienta KJ, Chinnaiyan AM, Wang Y, Collins CC, Gleave ME, Demichelis F, Nanus DM, Rubin MA. Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discov. 2011;1(6):487-495. DOI: 10.1158/2159-8290.CD-11-0130Chen R, Dong X, Gleave M. Molecular model for neuroendocrine prostate cancer progression. BJU Int. 2018;122(4):560-570. DOI: 10.1111/bju.14207Chen R, Dong X, Gleave M. Molecular model for neuroendocrine prostate cancer progression. BJU Int. 2018;122(4):560-570. DOI: 10.1111/bju.14207

The authors declare that there are no conflicts of interest present.