Current strategies for targeting the activity of androgen receptor variants

Current therapies for advanced prostate cancer, such as enzalutamide and abiraterone, focus on inhibiting androgen receptor (AR) activity and reducing downstream signaling pathways to inhibit tumor growth. Unfortunately, cancer cells are very adaptable and, over time, these cells develop mechanisms by which they can circumvent therapeutics. One of the many mechanisms that have been discovered is the generation of AR variants. These variants are generated through alternative splicing of the full length AR and often lack the ligand binding domain. This leads to forms of the AR that are constitutively active that continue to promote prostate cancer cell growth even in the absence of ligand. The high prevalence of AR variants and their role in disease progression have prompted a number of studies investigating ways to inhibited AR variant expression and activity. Among these are the anti-helminthic drug, niclosamide, which selectively promotes degradation of AR variants over full length AR and re-sensitizes anti-androgen resistant prostate cancer cells to treatment with enzalutamide and abiraterone. Other AR variant targeting mechanisms include interfering with AR variant co-activators and the development of drugs that bind to the DNA or N-terminal AR domains, which are retained in most AR variants. The clinical efficacy of treating prostate cancer by targeting AR variants is under investigation in several clinical trials. In this review, we provide an overview of the most relevant AR variants and discuss current AR variant targeting strategies.