Bypassing drug-resistance mechanisms of prostate cancer with small-molecules that target androgen receptor chromatin interactions

Human androgen receptor (AR) is a hormone-activated transcription factor that is an important drug-target in the treatment of prostate cancer. Current small molecule AR-antagonists (such as Enzalutamide) compete with male hormones that bind to the steroid binding pocket of the AR ligand binding domain (LBD). In castration-resistant prostate cancer (CRPC), drug-resistance can manifest through AR-LBD mutations that convert AR-antagonists into agonists, or by expression of AR-variants lacking the LBD. Such treatment resistance underscores the importance of novel ways of targeting the AR. In this study, we tested whether VPC14449, a small molecule inhibitor that was rationally designed to selectively target the AR DNA binding domain (DBD), could directly interfere with AR-DNA interactions. Using ChIP-seq in cell line models expressing AR or AR variants, we found that genome-wide chromatin binding of AR was dramatically impacted by VPC14449 (although with lesser effect on AR variants). AR and AR variant ChIP-seq in R1-AD1 and R1-D567 prostate cancer cells with VPC14449 treatment