Androgen receptor splice variant D567es (AR-v567es) (AR-v567es)

The Androgen receptor splice variant D567es (AR-v567es) is a truncated, constitutively active isoform of the androgen receptor (AR) that arises from the alternative splicing of AR pre-mRNA, specifically the skipping of exons 5, 6, and 7 (Sun et al., 2010, J Clin Invest). This deletion results in a protein that lacks the C-terminal ligand-binding domain (LBD) but retains the N-terminal transactivation domain and the DNA-binding domain (Liu et al., 2014, Cancer Res). Because the LBD is absent, the receptor does not require androgens like dihydrotestosterone for activation and is inherently resistant to conventional androgen deprivation therapies and LBD-targeting antagonists such as enzalutamide (Antonarakis et al., 2014, N Engl J Med). AR-v567es localizes to the nucleus where it drives the transcription of genes involved in cell cycle progression and survival, thereby promoting the development of castration-resistant prostate cancer (CRPC) (Myung et al., 2013, J Clin Invest). It is frequently detected in patients with advanced, metastatic disease and serves as a significant biomarker for poor prognosis and resistance to second-generation hormonal therapies (Hörnberg et al., 2011, PLoS One). Therapeutic efforts are currently focused on developing inhibitors that target the N-terminal domain (NTD), such as EPI-7386, or promote the degradation of the receptor to overcome this resistance mechanism (ClinicalTrials.gov, NCT04421222).

Other names

ARv567esAndrogen receptor variant 567esAR-V12AR-delta567es

Inhibition of the N-terminal domain (NTD) to block constitutive transcriptional activity.