Diverse AR Gene Rearrangements Mediate Resistance to Androgen Receptor Inhibitors in Metastatic Prostate Cancer.
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ICR Authors
Authors
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
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
Document Type
Journal Article
Date
2020-04-15
Date Accepted
2020-01-09
Abstract
PURPOSE: 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. EXPERIMENTAL DESIGN: 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 AR locus. We used genome engineering to perform experimental modeling of AR gene rearrangements and long-read RNA sequencing to analyze effects on expression of AR and truncated AR variants (AR-V). RESULTS: AR was among the most frequently rearranged genes in CRPC tumors. AR gene rearrangements promoted expression of diverse AR-V species. AR gene rearrangements occurring in the context of AR amplification correlated with AR overexpression. Cell lines with experimentally derived AR gene rearrangements displayed high expression of tumor-specific AR-Vs and were resistant to endocrine therapies, including the AR antagonist enzalutamide. CONCLUSIONS: AR gene rearrangements are an important mechanism of resistance to endocrine therapies in CRPC.
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2020, 26 (8), pp. 1965 - 1976
Source Title
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
1078-0432
eISSN
1557-3265
Collections
Research Team
Cancer Biomarkers
Prostate Cancer Targeted Therapy Group
Prostate Cancer Targeted Therapy Group