Androgen receptor (AR) inhibition is standard of care for advanced prostate cancer (PC). However, efficacy is limited by progression to castration-resistant PC (CRPC), usually due to AR re-activation via mechanisms that include AR amplification and structural rearrangement. These two classes of AR alterations often co-occur in CRPC tumors, but it is unclear whether this reflects intercellular or intracellular heterogeneity of AR. Resolving this is important for developing new therapies and predictive biomarkers. Here, we analyzed 41 CRPC tumors and 6 patient-derived xenografts (PDXs) using linked-read DNA-sequencing, and identified 7 tumors that developed complex, multiply-rearranged AR gene structures in conjunction with very high AR copy number. Analysis of PDX models by optical genome mapping and fluorescence in situ hybridization showed that AR residing on extrachromosomal DNA (ecDNA) was an underlying mechanism, and was associated with elevated levels and diversity of AR expression. This study identifies co-evolution of AR gene copy number and structural complexity via ecDNA as a mechanism associated with endocrine therapy resistance.
NAR cancer. 2023 Aug 24*** epublish ***
Andrej Zivanovic, Jeffrey T Miller, Sarah A Munro, Todd P Knutson, Yingming Li, Courtney N Passow, Pijus Simonaitis, Molly Lynch, LeAnn Oseth, Shuang G Zhao, Felix Y Feng, Pernilla Wikström, Eva Corey, Colm Morrissey, Christine Henzler, Benjamin J Raphael, Scott M Dehm
Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA., Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN, USA., University of Minnesota Genomics Center, University of Minnesota, Minneapolis, MN, USA., Department of Computer Science, Princeton University, Princeton, NJ, USA., Department of Human Oncology, University of Wisconsin-Madison, Madison, WI, USA., Departments of Radiation Oncology, Urology, and Medicine, University of California San Francisco, San Francisco, CA, USA., Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden., Department of Urology, University of Washington, Seattle, WA, USA.