Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer

H Beltran, D Prandi, JM Mosquera, M Benelli, L Puca… - Nature medicine, 2016 - nature.com
Nature medicine, 2016nature.com
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 …
Abstract
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.
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