Divergent clonal evolution of castration resistant neuroendocrine prostate cancer

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Abstract

An increasingly recognized resistance mechanism to androgen receptor (AR)-directed therapy in prostate cancer involves epithelial plasticity, wherein tumor cells demonstrate low to absent AR expression and often neuroendocrine features. The etiology and molecular basis for these “alternative” treatment-resistant cell states remain incompletely understood. Here, by analyzing whole exome sequencing data of metastatic biopsies from patients, we observed significant genomic overlap between castration resistant adenocarcinoma (CRPC-Adeno) and neuroendocrine histologies (CRPC-NE); analysis of serial progression samples points to a model most consistent with divergent clonal evolution. Genome-wide DNA methylation revealed marked epigenetic differences between CRPC-NE and CRPC-Adeno that also designated cases 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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Most cited references 41

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The clonal evolution of tumor cell populations.

P C Nowell (1976)

It is proposed that most neoplasms arise from a single cell of origin, and tumor progression results from acquired genetic variability within the original clone allowing sequential selection of more aggressive sublines. Tumor cell populations are apparently more genetically unstable than normal cells, perhaps from activation of specific gene loci in the neoplasm, continued presence of carcinogen, or even nutritional deficiencies within the tumor. The acquired genetic insta0ility and associated selection process, most readily recognized cytogenetically, results in advanced human malignancies being highly individual karyotypically and biologically. Hence, each patient's cancer may require individual specific therapy, and even this may be thwarted by emergence of a genetically variant subline resistant to the treatment. More research should be directed toward understanding and controlling the evolutionary process in tumors before it reaches the late stage usually seen in clinical cancer.

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Using microarray-based profiling of isogenic prostate cancer xenograft models, we found that a modest increase in androgen receptor mRNA was the only change consistently associated with the development of resistance to antiandrogen therapy. This increase in androgen receptor mRNA and protein was both necessary and sufficient to convert prostate cancer growth from a hormone-sensitive to a hormone-refractory stage, and was dependent on a functional ligand-binding domain. Androgen receptor antagonists showed agonistic activity in cells with increased androgen receptor levels; this antagonist-agonist conversion was associated with alterations in the recruitment of coactivators and corepressors to the promoters of androgen receptor target genes. Increased levels of androgen receptor confer resistance to antiandrogens by amplifying signal output from low levels of residual ligand, and by altering the normal response to antagonists. These findings provide insight toward the design of new antiandrogens.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9502015

Journal ID (pubmed-jr-id): 8791

Journal ID (nlm-ta): Nat Med

Journal ID (iso-abbrev): Nat. Med.

Title: Nature medicine

ISSN (Print): 1078-8956

ISSN (Electronic): 1546-170X

Publication date Nihms-submitted: 13 February 2016

Publication date (Electronic): 08 February 2016

Publication date (Print): March 2016

Publication date PMC-release: 08 August 2016

Volume: 22

Issue: 3

Pages: 298-305

Affiliations

[1 ] Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine. New York, NY

[2 ] Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine. New York, NY

[3 ] Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. New York, NY

[4 ] Centre for Integrative Biology, University of Trento. Trento, Italy

[5 ] Department of Pathology and Laboratory Medicine. Weill Cornell Medicine. New York, NY

[6 ] Department of Physiology and Biophysics. Weill Cornell Medicine. New York, NY

[7 ] Department of Pathology, University of Alabama, Birmingham, AL

[8 ] Department of Pathology, University of Michigan. Ann Arbor, MI

[9 ] Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA

[10 ] The Broad Institute of MIT and Harvard, Boston, MA

[11 ]Institute for Computational Biomedicine, Weill Cornell Medicine. New York, NY

Author notes

[#]

co-first authorship

[*]

co-senior authorship

Corresponding Authors: Himisha Beltran, MD, hip9004@ 123456med.cornell.edu , Mark A. Rubin, MD, rubinma@ 123456med.cornell.edu , Francesca Demichelis, PhD, f.demichelis@ 123456unitn.it

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Manuscript ID: NIHMS751180

DOI: 10.1038/nm.4045

PMC ID: 4777652

PubMed ID: 26855148

SO-VID: 9275b28f-9b4b-4d06-8502-5e378437ee02

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Divergent clonal evolution of castration resistant neuroendocrine prostate cancer

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Abstract

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Karger: Ophthalmology

Most cited references 41

The clonal evolution of tumor cell populations.

Molecular determinants of resistance to antiandrogen therapy.

Oncotator: cancer variant annotation tool.

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