An increasingly recognized resistance mechanism to androgen receptor (AR)-directed therapy in prostate cancer involves epithelial plasticity, in which tumor cells demonstrate low to absent AR expression and often have neuroendocrine features. The etiology and molecular basis for this ‘alternative’ treatment-resistant cell state remain incompletely understood. Here, by analyzing whole-exome sequencing data of metastatic biopsies from patients, we observed substantial genomic overlap between castration-resistant tumors that were histologically characterized as prostate adenocarcinomas (CRPC-Adeno) and neuroendocrine prostate cancer (CRPC-NE); analysis of biopsy samples from the same individuals over time points to a model most consistent with divergent clonal evolution. Genome-wide DNA methylation analysis revealed marked epigenetic differences between CRPC-NE tumors and CRPC-Adeno, and also designated samples of CRPC-Adeno with clinical features of AR independence as CRPC-NE, suggesting that epigenetic modifiers may play a role in the induction and/or maintenance of this treatment-resistant state. This study supports the emergence of an alternative, ‘AR-indifferent’ cell state through divergent clonal evolution as a mechanism of treatment resistance in advanced prostate cancer.

Nature medicine. 2016 Feb 08 [Epub]

Himisha Beltran, Davide Prandi, Juan Miguel Mosquera, Matteo Benelli, Loredana Puca, Joanna Cyrta, Clarisse Marotz, Eugenia Giannopoulou, Balabhadrapatruni V S K Chakravarthi, Sooryanarayana Varambally, Scott A Tomlins, David M Nanus, Scott T Tagawa, Eliezer M Van Allen, Olivier Elemento, Andrea Sboner, Levi A Garraway, Mark A Rubin, Francesca Demichelis

Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine, New York, New York, USA., Centre for Integrative Biology, University of Trento, Trento, Italy., Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York, USA., Department of Pathology, University of Alabama, Birmingham, Alabama, USA., Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA., Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, New York, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.