AR Structural Variants and Prostate Cancer

Abstract

Therapeutic interventions for advanced castration-resistant prostate cancer (CRPC) are focused on inhibiting the androgen receptor (AR) through targeting of its C-terminal ligand binding domain (LBD). However, a significant subset of CRPC patients demonstrate primary resistance to androgen deprivation and anti-androgen therapies, suggesting that other targets, outside of the AR, might be pertinent to the cancer progression. One explanation is the expression of androgen receptor splice variants (AR-Vs). So far, more than 20 AR-Vs have been identified from both prostate cancer cell lines and prostate cancer tissue biopsies. Most of the AR-Vs have a conserved N-terminal domain, but lack the LBD, yet retain the ability to bind DNA and activate downstream signaling. Although it remains unclear whether AR-Vs are principal divers or mere bystanders of CRPC progression, inhibiting AR-Vs, through drugs that target the AR transactivation function outside of the LBD, has been a major emphasis for next generation therapeutics in prostate cancer. This book chapter is dedicated to the role of AR variants and their clinical importance. We will review the initial discovery of AR-Vs, their regulation and prevalence, as well as their biological function in prostate cancer. We will provide an overview of the role of AR-Vs in the development of metastatic CRPC and in promoting clinical treatment failures. Lastly, we will present an introduction to the therapeutic approaches towards developing AR-V-targeted therapies including the continuing progress, the old challenges, and the new prospects.

Keywords: AR variants; Androgen receptor (AR); Degraders; Prostate cancer (PCa); Small molecule inhibitors.