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Diverse <i>AR</i> Gene Rearrangements Mediate Resistance to Androgen Receptor Inhibitors in Metastatic Prostate Cancer.

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Publication Date
2020-04
ICR Author
Carreira, Suzanne
De Bono, Johann
Author
Li, Y
Yang, R
Henzler, CM
Ho, Y
Passow, C
Auch, B
Carreira, S
Nava Rodrigues, D
Bertan, C
Hwang, TH
Quigley, DA
Dang, HX
Morrissey, C
Fraser, M
Plymate, SR
Maher, CA
Feng, FY
de Bono, JS
Dehm, SM
Type
Journal Article
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Abstract
<b>Purpose: </b>Prostate cancer is the second leading cause of male cancer deaths. Castration-resistant prostate cancer (CRPC) is a lethal stage of the disease that emerges when endocrine therapies are no longer effective at suppressing activity of the androgen receptor (AR) transcription factor. The purpose of this study was to identify genomic mechanisms that contribute to the development and progression of CRPC.<br><br><b>Experimental design: </b>We used whole-genome and targeted DNA-sequencing approaches to identify mechanisms underlying CRPC in an aggregate cohort of 272 prostate cancer patients. We analyzed structural rearrangements at the genome-wide level and carried out a detailed structural rearrangement analysis of the <i>AR</i> locus. We used genome engineering to perform experimental modeling of <i>AR</i> gene rearrangements and long-read RNA sequencing to analyze effects on expression of AR and truncated AR variants (AR-V).<br><br><b>Results: </b><i>AR</i> was among the most frequently rearranged genes in CRPC tumors. <i>AR</i> gene rearrangements promoted expression of diverse AR-V species. <i>AR</i> gene rearrangements occurring in the context of <i>AR</i> amplification correlated with AR overexpression. Cell lines with experimentally derived <i>AR</i> gene rearrangements displayed high expression of tumor-specific AR-Vs and were resistant to endocrine therapies, including the AR antagonist enzalutamide.<br><br><b>Conclusions: </b><i>AR</i> gene rearrangements are an important mechanism of resistance to endocrine therapies in CRPC.
URL
https://repository.icr.ac.uk/handle/internal/3531
Collections
  • Cancer Therapeutics
  • Clinical Studies
Licenseref URL
http://www.rioxx.net/licenses/under-embargo-all-rights-reserved
Version of record
10.1158/1078-0432.ccr-19-3023
Research team
Cancer Biomarkers
Prostate Cancer Targeted Therapy Group
Language
eng
Date accepted
2020-01-09
License start date
2020-04
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2020, 26 (8), pp. 1965 - 1976

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