Internal medicine

Phenotype

Cell

Enzalutamide

Prostate cancer

Bioinformatics

Androgen receptor

Biology

Gene

Cancer

Oncology

Prostate

Neuroendocrine differentiation

Cancer research

Genetics

Medicine

Reprogramming

Nature Reviews Urology

Neuroendocrine prostate cancers (NEPCs) are androgen independent and aggressive and have characteristics of epithelial–mesenchymal plasticity and stem-like cell properties. This Review describes the link between lineage plasticity and an emergent NEPC phenotype and how this knowledge can aid in the development of novel therapeutics. 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.

Cellular plasticity and the neuroendocrine phenotype in prostate cancer