Molecular mechanisms underlying the development of neuroendocrine prostate cancer

Prostate cancer is the most common non-cutaneous cancer and the second leading cause of cancer-associated deaths among men in the United States. Androgen deprivation therapy (ADT) is the standard of care for advanced prostate cancer. While patients with advanced prostate cancer initially respond to ADT, the disease frequently progresses to a lethal metastatic form, defined as castration-resistant prostate cancer (CRPC). After multiple rounds of anti-androgen therapies, 20-25% of metastatic CRPCs develop a neuroendocrine (NE) phenotype. These tumors are classified as neuroendocrine prostate cancer (NEPC). De novo NEPC is rare and accounts for less than 2% of all prostate cancers at diagnosis. NEPC is commonly characterized by the expression of NE markers and the absence of androgen receptor (AR) expression. NEPC is usually associated with tumor aggressiveness, hormone therapy resistance, and poor clinical outcome. Here, we review the molecular mechanisms underlying the emergence of NEPC and provide insights into the future perspectives on potential therapeutic strategies for NEPC.