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Molecular Characterization of Neuroendocrine Prostate Cancer and Identification of New Drug Targets

2011; American Association for Cancer Research; Volume: 1; Issue: 6 Linguagem: Inglês

10.1158/2159-8290.cd-11-0130

2159-8290

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 Gerstein, Sven Perner, Kenneth J. Pienta, Arul M. Chinnaiyan, Yuzhuo Wang, Colin C. Collins, Martin Gleave, Francesca Demichelis, David M. Nanus, Mark A. Rubin,

Ubiquitin and proteasome pathways

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.