Comprehensive genomics in androgen receptor-dependent castration-resistant prostate cancer using a patient-derived xenograft and cell lines

Castration resistance is a lethal form of treatment failure of prostate cancer (PCa) and is associated with activation of the androgen receptor (AR). It is only partially understood how the AR mediates survival and castration-resistant growth of PCa upon androgen deprivation. We investigated integrative genomics (including gene expression and ARBS profiling) using a patient-derived xenograft (PDX) model recapitulating acquired, AR-dependent castration-resistant PCa (CRPC). Sequencing of chromatin immunoprecipitation using an anti-AR antibody (AR ChIP-seq) revealed distinct profiles of AR binding site (ARBS) in androgen-dependent (AD) and castration-resistant (CR) xenograft tumors compared with those previously reported based on human PCa cells or tumor tissues. To search candidate genes for a therapeutic target in CRPC, we combined RNA-seq analysis using PDX AD and CR tumors with the results from AR ChIP seq. This analysis identified several AR-target genes associated with CRPC progression including OPRK1, which harbors ARBS and was upregulated upon androgen deprivation.