Abstract
Overexpression of MYCN in normal basal prostate cells drives formation of metastatic NEPC.
Major finding: Overexpression of MYCN in normal basal prostate cells drives formation of metastatic NEPC.
Clinical relevance: Aurora A kinase inhibitors downregulate MYCN and reduce MYCN-driven NEPC growth.
Impact: MYCN upregulation during prostate cancer progression may drive conversion to NEPC.
Neuroendocrine prostate cancer (NEPC) characterized by a heterogeneous morphology and expression of neuroendocrine differentiation markers can evolve from prostate adenocarcinoma during androgen-deprivation therapy and has a particularly poor prognosis. Unlike prostate adenocarcinomas, NEPCs exhibit frequent amplification or overexpression of MYCN, prompting Lee and colleagues to investigate whether MYCN plays a role in the development and maintenance of NEPC. In a model of premalignant prostatic intraepithelial neoplasia in which active myristoylated AKT1 (myrAKT1) is overexpressed, forced expression of MYCN in normal prostate basal cells, but not in luminal cells, led to the formation of invasive, metastatic castration-resistant tumors that were positive for neuroendocrine markers. Analysis of gene expression in MYCN/myrAKT1-driven prostate tumors revealed gene signatures previously identified in human NEPC tumors, including low expression of androgen-regulated genes and epithelial markers, and high levels of endocrine markers, MYCN, and the cell cycle regulator Aurora kinase A (AURKA). Limiting dilution experiments indicated that transformed MYCN/myrAKT1 cells had high tumor-initiating capacity and gave rise to tumors with biphenotypic NEPC and adenocarcinoma histology. Moreover, MYCN was also required for maintenance of these tumors. In line with these findings suggesting that NEPC is dependent on MYCN and that MYCN might be an attractive therapeutic target in these tumors, treatment of MYCN/myrAKT1 tumor-derived cells with an inhibitor of AURKA, which has been shown to stabilize MYCN, led to apoptosis in vitro and reduced tumor burden in vivo in association with increased MYCN protein degradation. Together, these results implicate MYCN as a driver of NEPC and provide a rationale for the potential therapeutic use of AURKA inhibitors in NEPC patients with high MYCN expression.