Androgen receptor and its splice variants in prostate cancer

Abstract

Androgen receptor (AR) is a transcription factor that becomes active upon binding to androgens via its ligand-binding domain (LBD) or in response to signaling cascades initiated by growth factors and cytokines. The activity of AR requires regions within the N-terminal domain (NTD) in a manner that is distinct from the activation of related steroid hormone receptors. Unequivocal evidence has been amassed to consider that the AR axis is the most critical pathway for the progression of prostate cancer. Qualitatively distinct insights into AR pathobiology have been garnered including that AR-regulated gene expression is stage-specifically modulated during disease progression and that the ligand requirement for AR activity could be rendered dispensable because of the expression of constitutively active AR splice variants that are devoid of LBD. The recent appreciation of the clinical challenge that stems from non-gonadal androgens that are not inhibited by traditional hormonal therapies has been tangibly translated into the development of more potent drugs that can potentially lead towards achieving an androgen-free environment. The pre-clinical evidence that proves that AR NTD is a druggable target also forecasts a further paradigm shift in the management of advanced prostate cancer. These advancements together with the identification of more robust AR antagonists and their promising clinical outcome have renewed the hope that targeting the AR pathway remains a sound strategy in the clinical management of prostate cancer. Here, we address these developments with a greater emphasis on the rapidly growing literature on AR splice variants.

Fig. 1

Drug targets of AR-mediated mechanisms underlying CPRC. Drugs known to directly bind AR or block enzymes catalyzing the synthesis of androgen are shown. EPI-001 is predicted to intercept with all facets of AR associated with CPRC due to the requirement of the NTD for AR transcriptional activity

Fig. 2

Variant transcripts and predicted or detected cognate protein products. Despite the uniform color code (red), the resulting predicted/detected peptide sequences are unique to each variant. Alternative names are indicated in gray font. Nomenclature of novel exons is based on the relative position in the AR locus. “dis” designates disrupted domain. Novel exons and related peptide sequences are indicated in red. Depictions are not to scale. Those variants that are reportedly detected in only one prostate cancer specimen or derivatives thereof are not shown