Molecular events in neuroendocrine prostate cancer development

• Published in: Nature reviews. Urology Vol. 18; no. 10; pp. 581 - 596
• Main Authors: Wang, Yong, Wang, Yu, Ci, Xinpei, Choi, Stephen Y. C., Crea, Francesco, Lin, Dong, Wang, Yuzhuo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2021; Nature Publishing Group
• Subjects: 631/208/68/2486; 631/67/589/466; Adenocarcinoma - drug therapy; Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Androgen Antagonists - therapeutic use; Androgens; Antineoplastic Agents - therapeutic use; Care and treatment; Cell receptors; Cell Transdifferentiation; Development and progression; Disease Progression; Gene expression; Genetic aspects; Health aspects; Humans; Male; Medicine; Medicine & Public Health; Neuroendocrine Tumors - genetics; Neuroendocrine Tumors - metabolism; Neuroendocrine Tumors - pathology; Phenotype; Platinum Compounds - therapeutic use; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - metabolism; Prostatic Neoplasms, Castration-Resistant - pathology; Receptors, Androgen - metabolism; Review Article; Urology; Canada
• ISSN: 1759-4812; 1759-4820; 1759-4820
• DOI: 10.1038/s41585-021-00490-0

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer. NEPC arises de novo only rarely; the disease predominantly develops from adenocarcinoma in response to drug-induced androgen receptor signalling inhibition, although the mechanisms behind this transdifferentiation are a subject of debate. The survival of patients with NEPC is poor, and few effective treatment options are available. To improve clinical outcomes, understanding of the biology and molecular mechanisms regulating NEPC development is crucial. Various NEPC molecular drivers make temporal contributions during NEPC development, and despite the limited treatment options available, several novel targeted therapeutics are currently under research. Neuroendocrine prostate cancer predominantly develops from adenocarcinoma following a period of androgen suppressive treatment. Outcomes in patients with this disease are poor; the understanding of the molecular mechanisms behind its development will improve future targeted therapy options. Key points Neuroendocrine prostate cancer (NEPC) is an aggressive variant form that is characterized by low or absent androgen receptor (AR) expression, gain of the neuroendocrine phenotype and is not responsive to therapies targeting AR signalling. De novo NEPC accounts for less than 2% of all prostate cancers, but treatment-induced NEPC occurs in 10–17% of patients with castration-resistant prostate cancer by evolving from adenocarcinoma, probably as a result of a transdifferentiation process. Molecular mechanisms underlying NEPC development include genomic alterations, abnormal regulation of epigenetic regulators, transcription factors and other molecular pathways. The temporal contribution and co-operation of NEPC drivers during adenocarcinoma to NEPC transdifferentiation is largely unknown; thus, longitudinal study of serial patient samples and preclinical models that recapitulate the entire disease progression is warranted. Longitudinal analyses of the only clinically relevant patient-derived xenograft model with serial genomic and transcriptomic data available throughout the adenocarcinoma-to-NEPC transdifferentiation process (LTL331/331 R) could group NEPC-driving molecular alterations into early and terminal events, suggesting their roles during different phases of NEPC development. Platinum-based chemotherapy is the only treatment currently available for NEPC. Advances in NEPC research have led to new potential therapies that are undergoing investigation in clinical trials or in preclinical development.