Metastatic prostate cancer is a complex and heterogeneous disease. To better understand drivers of this disease, we performed deep whole genome sequencing, transcriptome sequencing, whole genome bisulfite sequencing, 5 hydroxy-methylsequencing, ATAC sequencing, and Hi-C sequencing on over 100 metastases from patients with disease resistant to first-line androgen deprivation therapies. Among many findings, we demonstrate that progression of disease is associated with amplifications of enhancers that increase expression of the androgen receptor (AR) in over 80% of patients, and that AR amplification occurs via circularization of the AR gene.
To better develop approaches for targeting AR, we created an endogeneous reporter of AR expression in prostate cancer cell lines. Using this reporter, we performed a genome-wide CRISPRi screen to understand regulators of AR, and identified prostaglandin E synthase 3 (PTGES3) as necessary for expression of AR. We identified a novel function for PTGES3 in regulating AR, and developed a novel small molecule tool compound for targeting PTGES3. These findings suggest that PTGES3 inhibition represents a potential approach for targeting AR.