Co-evolution of <i>AR</i> gene copy number and structural complexity in endocrine therapy resistant prostate cancer

Abstract

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 <i>AR</i> amplification and structural rearrangement. These two classes of <i>AR</i> alterations often co-occur in CRPC tumors, but it is unclear whether this reflects intercellular or intracellular heterogeneity of <i>AR</i>. 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 <i>AR</i> gene structures in conjunction with very high <i>AR</i> copy number. Analysis of PDX models by optical genome mapping and fluorescence <i>in situ</i> hybridization showed that <i>AR</i> 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 <i>AR</i> gene copy number and structural complexity via ecDNA as a mechanism associated with endocrine therapy resistance.