ReviewC-terminally truncated constitutively active androgen receptor variants and their biologic and clinical significance in castration-resistant prostate cancer

•ARΔLBDs are products of alternative splicing (AR-V), premature stop codons (Q641X) or enzymatic cleavage (tr-AR).•ARΔLBDs can be subdivided into two structurally and functionally distinct subgroups, depending on the presence/absence of a hinge region.•Various ARΔLBDs are involved in PCa progression (castration resistance, EMT, glutaminolysis etc).•ARΔLBDs like AR-V7 are highly interesting new prognostic and therapeutic targets.

A mechanism allowing castration resistant prostate cancer cells to escape the effects of conventional anti-hormonal treatments is the synthesis of constitutively active, C-terminally truncated androgen receptor (AR)-variants. Lacking the entire or vast parts of the ligand binding domain, the intended target of traditional endocrine therapies, these AR-variants (termed ARΔLBD) are insensitive to all traditional treatments including second generation compounds like abiraterone, enzalutamide or ARN-509. Although ARΔLBD are predominantly products of alternative splicing, they can also be products of nonsense mutations or proteolytic cleavage. In this review, we will discuss the etiology and function of c-terminally truncated AR-variants and their clinical significance as markers/targets for the treatment of castration resistant prostate cancer.