title: Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: Himisha
authors.initials: H
authors.lastname: Beltran
authors.forename: David S
authors.initials: DS
authors.lastname: Rickman
authors.forename: Kyung
authors.initials: K
authors.lastname: Park
authors.forename: Sung Suk
authors.initials: SS
authors.lastname: Chae
authors.forename: Andrea
authors.initials: A
authors.lastname: Sboner
authors.forename: Theresa Y
authors.initials: TY
authors.lastname: MacDonald
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Wang
authors.forename: Karen L
authors.initials: KL
authors.lastname: Sheikh
authors.forename: Stéphane
authors.initials: S
authors.lastname: Terry
authors.forename: Scott T
authors.initials: ST
authors.lastname: Tagawa
authors.forename: Rajiv
authors.initials: R
authors.lastname: Dhir
authors.forename: Joel B
authors.initials: JB
authors.lastname: Nelson
authors.forename: Alexandre
authors.initials: A
authors.lastname: de la Taille
authors.forename: Yves
authors.initials: Y
authors.lastname: Allory
authors.forename: Mark B
authors.initials: MB
authors.lastname: Gerstein
authors.forename: Sven
authors.initials: S
authors.lastname: Perner
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Pienta
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
authors.forename: Yuzhuo
authors.initials: Y
authors.lastname: Wang
authors.forename: Colin C
authors.initials: CC
authors.lastname: Collins
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.forename: Francesca
authors.initials: F
authors.lastname: Demichelis
authors.forename: David M
authors.initials: DM
authors.lastname: Nanus
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D064096:Aurora Kinase A; D064127:Aurora Kinases; D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015331:Cohort Studies; D018450:Disease Progression; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy; D000071447:N-Myc Proto-Oncogene Protein; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011467:Prostate / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D047428:Protein Kinase Inhibitors; C576917:AURKA protein, human; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases