SRA

The androgen receptor (AR) antagonist darolutamide has very recently been approved for the treatment of non-metastatic castration resistant prostate cancer (PCa). Here we determined the genome-wide effects of darolutamide on cis-acting regulatory elements involved in androgen signaling with a focus on enhancer and super-enhancer (SE) regions. Darolutamide strongly depleted the AR from regulatory elements and abolished the AR transcriptional signaling. Using two different androgen-dependent PCa cell lines we identified genomic-regions with different affinities for the AR in androgen-stimulated, androgen-depleted and darolutamide-antagonized conditions. Altogether, our findings demonstrate that darolutamide is a potent AR antagonist blocking genome-wide AR signaling and AR enhancer activation. Further, we show a dynamic AR cistrome and concomitant adapting chromatin environment to varying conditions and identified regions with high AR affinity in cell lines and tissue samples. Overall design: Prostate androgen-sensitive cell lines VCaP and LAPC-4 were grown for two days in starvation medium prior to treatment with DMSO control, synthetic androgen R1881 at a concentration of 1 nM or R1881 with darolutamide at a concentration of 500 nM (low) or 2 µM (high). The cells were harvested 8 h or 22 h post-induction for RNA isolation and sequencing.