Diverse AR Gene Rearrangements Mediate Resistance to Androgen Receptor Inhibitors in Metastatic Prostate Cancer

• Published in: Clinical cancer research Vol. 26; no. 8; pp. 1965 - 1976
• Main Authors: Li, Yingming, Yang, Rendong, Henzler, Christine M., Ho, Yeung, Passow, Courtney, Auch, Benjamin, Carreira, Suzanne, Nava Rodrigues, Daniel, Bertan, Claudia, Hwang, Tae Hyun, Quigley, David A., Dang, Ha X., Morrissey, Colm, Fraser, Michael, Plymate, Stephen R., Maher, Christopher A., Feng, Felix Y., de Bono, Johann S., Dehm, Scott M.
• Format: Journal Article
• Language: English
• Published: United States 15.04.2020
• Subjects: Androgen Receptor Antagonists - pharmacology; Benzamides; Biomarkers, Tumor - genetics; Cell Line, Tumor; Drug Resistance, Neoplasm - genetics; Gene Rearrangement; Humans; Male; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin - analogs & derivatives; Phenylthiohydantoin - pharmacology; Prospective Studies; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - pathology; Receptors, Androgen - chemistry; Receptors, Androgen - genetics; Whole Genome Sequencing - methods
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-19-3023

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. 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 locus. We used genome engineering to perform experimental modeling of gene rearrangements and long-read RNA sequencing to analyze effects on expression of AR and truncated AR variants (AR-V). was among the most frequently rearranged genes in CRPC tumors. gene rearrangements promoted expression of diverse AR-V species. gene rearrangements occurring in the context of amplification correlated with AR overexpression. Cell lines with experimentally derived gene rearrangements displayed high expression of tumor-specific AR-Vs and were resistant to endocrine therapies, including the AR antagonist enzalutamide. gene rearrangements are an important mechanism of resistance to endocrine therapies in CRPC.