Molecular features of prostate cancer with neuroendocrine differentiation

Prostate cancer (PCa) is a biologically diverse malignancy with a clinical trajectory that often culminates in treatment resistance and aggressive phenotypes. Among these, neuroendocrine prostate cancer (NEPC) represents a particularly lethal variant that arises either de novo or through transdifferentiation from conventional adenocarcinoma under therapeutic pressure. This review summarizes the recent advances in our understanding of neuroendocrine differentiation in prostate cancer. We review the genetic, epigenetic, and transcriptional drivers of lineage plasticity, including key roles for TP53, RB1, EZH2, MYCN, and REST, and highlight emerging entities such as amphicrine prostate cancers. Furthermore, we discuss the evolving WHO classification, diagnostic challenges, and therapeutic strategies targeting NEPC, including PARP inhibitors (DNA damage repair-deficient subsets), Aurora kinase inhibitors (N-Myc/AURKA activation), and DLL3-directed approaches.