Title | Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. |
Publication Type | Journal Article |
Year of Publication | 2011 |
Authors | Beltran H, Rickman DS, Park K, Chae SSuk, Sboner A, MacDonald TY, Wang Y, Sheikh KL, Terry S, Tagawa ST, Dhir, iv R, Nelson JB, de la Taille A, Allory Y, Gerstein MB, Perner S, Pienta KJ, Chinnaiyan AM, Wang Y, Collins CC, Gleave ME, Demichelis F, Nanus DM, Rubin MA |
Journal | Cancer Discov |
Volume | 1 |
Issue | 6 |
Pagination | 487-95 |
Date Published | 2011 Nov |
ISSN | 2159-8290 |
Keywords | 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, Neuroendocrine Tumors, Nuclear Proteins, Oncogene Proteins, Prostate, Prostatic Neoplasms, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases |
Abstract | UNLABELLED: 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. |
DOI | 10.1158/2159-8290.CD-11-0130 |
Alternate Journal | Cancer Discov |
PubMed ID | 22389870 |
PubMed Central ID | PMC3290518 |
Grant List | P50 CA69568 / CA / NCI NIH HHS / United States R01 CA116337 / CA / NCI NIH HHS / United States R01 CA116337-01A1 / CA / NCI NIH HHS / United States R01 CA125612 / CA / NCI NIH HHS / United States R01 CA125612-01A1 / CA / NCI NIH HHS / United States R01-125612 / / PHS HHS / United States R01-CA116337 / CA / NCI NIH HHS / United States U01 CA111275 / CA / NCI NIH HHS / United States |