51. Understanding the Lethal Variant of Prostate Cancer: Power of Examining Extremes
- Author
-
Ana Aparicio, Christopher J. Logothetis, and Sankar N. Maity
- Subjects
Male ,medicine.medical_specialty ,Cell ,Gene Expression ,Antineoplastic Agents ,Disease ,Adenocarcinoma ,Protein Serine-Threonine Kinases ,Neuroendocrine tumors ,Biology ,Proto-Oncogene Mas ,Article ,Cohort Studies ,Prostate cancer ,Aurora Kinases ,Prostate ,Cell Line, Tumor ,Internal medicine ,medicine ,Humans ,Molecular Targeted Therapy ,Carcinoma, Small Cell ,Protein Kinase Inhibitors ,Aurora Kinase A ,Oncogene Proteins ,N-Myc Proto-Oncogene Protein ,Nuclear Proteins ,Prostatic Neoplasms ,Prostate carcinoma ,medicine.disease ,Neuroendocrine Tumors ,medicine.anatomical_structure ,Endocrinology ,Oncology ,Disease Progression ,Cancer research - 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.
- Published
- 2011