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

Himisha Beltran, David S. Rickman, Kyung Park, Sung Suk Chae, Andrea Sboner, Theresa Y. MacDonald, Yuwei Wang, Karen L. Sheikh, Stéphane Terry, Scott T. Tagawa, Rajiv Dhir, Joel B. Nelson, Alexandre de la Taille, Yves Allory, Mark B. Gerstein, Sven Perner, Kenneth J. Pienta, Arul M. Chinnaiyan, Yuzhuo Wang, Colin C. CollinsMartin E. Gleave, Francesca Demichelis, David M. Nanus, Mark A. Rubin

365 Citations (Scopus)


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) samples and validated findings in tumors from a large cohort of patients (37 with NEPC, 169 with PCA, and 22 with BEN) using immunohistochemistry and FISH. We discovered significant overexpression and gene amplification of AURKA and MYCN in 40% of NEPC and 5% of PCA tumors, respectively, and evidence 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 that future clinical trials will help determine 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.

Original languageEnglish
JournalCancer Discovery
Issue number6
Pages (from-to)487-495
Number of pages9
Publication statusPublished - 01.11.2011


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