Genetic and epigenetic mechanisms underlying treatment-induced neuroendocrine prostate cancer

Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a lethal subtype of castration-resistant prostate cancer (CRPC) characterized by unique pathological features and molecular changes, including the loss of androgen receptor (AR) activities and the gain of neuroendocrine gene expression. The incidence of t-NEPC has increased substantially in the last decade, in up to 20 % of CRPC cases, largely due to intensive treatment of advanced prostate cancer (PCa) with AR pathway inhibitors (ARPi). While genomic alterations between CRPC and t-NEPC are largely conserved, their epigenetic programs are markedly distinct. The molecular mechanisms underlying the neuroendocrine transformation (NET) of PCa are rapidly emerging. Here, we first briefly summarize the genetic drivers of t-NEPC and then comprehensively review 2D and 3D chromatin alterations, including changes in DNA methylation, histone modifications, chromatin accessibility, and 3D chromatin organization, during NET of PCa. We then review key molecular regulators, including lineage-specific transcription factors and chromatin modifiers, of such epigenetic programs. Lastly, we discuss evidence that suggests a mixed model of clonal selection and transformation that underlies NEPC progression.