Diverse AR gene rearrangements mediate resistance to androgen receptor inhibitors in metastatic prostate cancer

Yingming Li, Rendong Yang, Christine M. Henzler, Yeung Ho, Courtney Passow, Benjamin Auch, Suzanne Carreira, Daniel Nava Rodrigues, Claudia Bertan, Tae Hyun Hwang, David A. Quigley, Ha X. Dang, Colm Morrissey, Michael Fraser, Stephen R. Plymate, Christopher A. PlymateMaher, Felix Y. Feng, Johann S. De Bono, Scott M. Dehm

Research output: Contribution to journalArticle

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 ofARandtruncatedARvariants (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 andwere resistant to endocrine therapies, including the AR antagonist enzalutamide. Conclusions: AR gene rearrangements are an important mechanism of resistance to endocrine therapies in CRPC.

Original languageEnglish (US)
Pages (from-to)1965-1976
Number of pages12
JournalClinical Cancer Research
Volume26
Issue number8
DOIs
StatePublished - Apr 15 2020
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Li, Y., Yang, R., Henzler, C. M., Ho, Y., Passow, C., Auch, B., Carreira, S., Rodrigues, D. N., Bertan, C., Hwang, T. H., Quigley, D. A., Dang, H. X., Morrissey, C., Fraser, M., Plymate, S. R., PlymateMaher, C. A., Feng, F. Y., De Bono, J. S., & Dehm, S. M. (2020). Diverse AR gene rearrangements mediate resistance to androgen receptor inhibitors in metastatic prostate cancer. Clinical Cancer Research, 26(8), 1965-1976. https://doi.org/10.1158/1078-0432.CCR-19-3023