Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets

Cancer Discov. 2011 Nov;1(6):487-95. doi: 10.1158/2159-8290.CD-11-0130.

Abstract

Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer that most commonly evolves from preexisting prostate adenocarcinoma (PCA). Using Next Generation RNA-sequencing and oligonucleotide arrays, we profiled 7 NEPC, 30 PCA, and 5 benign prostate tissue (BEN), and validated findings on tumors from a large cohort of patients (37 NEPC, 169 PCA, 22 BEN) using IHC and FISH. We discovered significant overexpression and gene amplification of AURKA and MYCN in 40% of NEPC and 5% of PCA, respectively, and evidence that that they cooperate to induce a neuroendocrine phenotype in prostate cells. There was dramatic and enhanced sensitivity of NEPC (and MYCN overexpressing PCA) to Aurora kinase inhibitor therapy both in vitro and in vivo, with complete suppression of neuroendocrine marker expression following treatment. We propose that alterations in Aurora kinase A and N-myc are involved in the development of NEPC, and future clinical trials will help determine from the efficacy of Aurora kinase inhibitor therapy.

Significance: We report on the largest in-depth molecular analysis of NEPC and provide new insight into molecular events involved in the progression of prostate cancer.

Keywords: aurora kinase A; drug targets; n-myc; neuroendocrine prostate cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Antineoplastic Agents / therapeutic use*
  • Aurora Kinase A
  • Aurora Kinases
  • Carcinoma, Small Cell / drug therapy
  • Carcinoma, Small Cell / genetics
  • Carcinoma, Small Cell / metabolism
  • Cell Line, Tumor
  • Cohort Studies
  • Disease Progression
  • Gene Expression / drug effects
  • Gene Expression / genetics
  • Humans
  • Male
  • Molecular Targeted Therapy
  • N-Myc Proto-Oncogene Protein
  • Neuroendocrine Tumors / drug therapy*
  • Neuroendocrine Tumors / genetics*
  • Neuroendocrine Tumors / metabolism
  • Neuroendocrine Tumors / pathology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism
  • Prostate / drug effects
  • Prostate / metabolism
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism

Substances

  • Antineoplastic Agents
  • MYCN protein, human
  • N-Myc Proto-Oncogene Protein
  • Nuclear Proteins
  • Oncogene Proteins
  • Protein Kinase Inhibitors
  • AURKA protein, human
  • Aurora Kinase A
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases