Molecular basis of neuroendocrine prostate cancer

Abstract

Although de-novo neuroendocrine prostate cancer (NEPC) is rare, with increasing use of potent androgen receptor (AR) pathway inhibitors, the incidence of treatment-related NEPC (t-NEPC) is rapidly rising. Since NEPC is an aggressive disease with poor prognosis, novel therapeutic strategies are urgently needed. Recent genomic and molecular analysis have identified key oncogenes (MYCN, AURKA) and tumor suppressor genes (TP53, RB1) to play key roles in driving NEPC. Novel in vivo and in vitro research models of NEPC were developed to serve as valuable resource to study functional relevance of the key genes in NEPC development. Upon AR pathway inhibition, these genomic alterations seem to facilitate epithelial plasticity by upregulating the genes implicated in maintaining pluripotency (SOX2, EZH2), resulting in development of divergent tumor including NEPC from castration resistant prostate cancer. Further understanding of the molecular biology is required to identify novel molecular targets and biomarkers that would help rescue patients from this lethal variant.