N-Myc Drives Neuroendocrine Prostate Cancer Initiated from Human Prostate Epithelial Cells

•N-Myc and AKT1 drive NEPC from human prostate epithelium•Prostate epithelial cells can give rise to neuroendocrine and epithelial cancers•N-Myc is essential for tumor maintenance in tumors initiated by N-Myc and AKT1•Destabilization of N-Myc through Aurora A kinase inhibition induces tumor cell death

SummaryMYCN amplification and overexpression are common in neuroendocrine prostate cancer (NEPC). However, the impact of aberrant N-Myc expression in prostate tumorigenesis and the cellular origin of NEPC have not been established. We define N-Myc and activated AKT1 as oncogenic components sufficient to transform human prostate epithelial cells to prostate adenocarcinoma and NEPC with phenotypic and molecular features of aggressive, late-stage human disease. We directly show that prostate adenocarcinoma and NEPC can arise from a common epithelial clone. Further, N-Myc is required for tumor maintenance, and destabilization of N-Myc through Aurora A kinase inhibition reduces tumor burden. Our findings establish N-Myc as a driver of NEPC and a target for therapeutic intervention.

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