mln-8237 and Cell-Transformation--Neoplastic

MYCN 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.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Aurora Kinase A; Azepines; Cell Line, Tumor; Cell Transformation, Neoplastic; Enzyme Activation; Epithelial Cells; Exome; Gene Expression Regulation, Neoplastic; Genes, myc; Humans; Laser Capture Microdissection; Male; Mice, Inbred NOD; Mice, SCID; Molecular Targeted Therapy; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Neoplastic Stem Cells; Neuroendocrine Tumors; Orchiectomy; Phenylurea Compounds; Prostatic Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Pyrimidines; Recombinant Fusion Proteins; Transduction, Genetic; Xenograft Model Antitumor Assays