Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Academic Article uri icon

Overview

MeSH

  • Adenocarcinoma
  • Aurora Kinase A
  • Aurora Kinases
  • Carcinoma, Small Cell
  • Cell Line, Tumor
  • Cohort Studies
  • Disease Progression
  • Gene Expression
  • Humans
  • Male
  • Molecular Targeted Therapy
  • N-Myc Proto-Oncogene Protein
  • Nuclear Proteins
  • Oncogene Proteins
  • Prostate
  • Protein-Serine-Threonine Kinases

MeSH Major

  • Antineoplastic Agents
  • Neuroendocrine Tumors
  • Prostatic Neoplasms
  • Protein Kinase Inhibitors

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. 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. © 2011 AACR.

publication date

  • November 2011

has subject area

  • Adenocarcinoma
  • Antineoplastic Agents
  • Aurora Kinase A
  • Aurora Kinases
  • Carcinoma, Small Cell
  • Cell Line, Tumor
  • Cohort Studies
  • Disease Progression
  • Gene Expression
  • Humans
  • Male
  • Molecular Targeted Therapy
  • N-Myc Proto-Oncogene Protein
  • Neuroendocrine Tumors
  • Nuclear Proteins
  • Oncogene Proteins
  • Prostate
  • Prostatic Neoplasms
  • Protein Kinase Inhibitors
  • Protein-Serine-Threonine Kinases

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3290518

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-11-0130

PubMed ID

  • 22389870

Additional Document Info

start page

  • 487

end page

  • 495

volume

  • 1

number

  • 6