Androgen receptor splice variant (AR-V) (AR-V)

C-terminally truncated androgen receptor (AR) variant mRNAs are alternative splice products of the AR gene that lack the C-terminal ligand-binding domain (LBD) (NIH, 2024). These variants, most notably AR-V7 and AR-V567es, encode constitutively active transcription factors that can drive the expression of AR-regulated genes even in the absence of androgens (MDPI, 2024). Their emergence is a primary mechanism of resistance to second-generation anti-androgens like enzalutamide and abiraterone, which target the LBD (PubMed, 2016). Because they lack the LBD, these variants are inherently resistant to conventional hormonal therapies (NIH, 2011). Therapeutic strategies currently under investigation include targeting the N-terminal domain (NTD) or DNA-binding domain (DBD), which are conserved in these variants, as well as using antisense oligonucleotides or spliceosome inhibitors to prevent the production of the truncated mRNAs (Encyclopedia.pub, 2024). Clinical detection of these variants, particularly AR-V7 in circulating tumor cells, serves as a critical biomarker for predicting poor response to standard androgen receptor-targeted agents (JAMA Oncology, 2015). Ongoing drug development focuses on small molecules that can bind the intrinsically disordered NTD to inhibit the transcriptional activity of both full-length and variant receptors (Journal of Clinical Investigation, 2013).

Other names

AR-V7AR-V567esAR-V1AR-V3AR-V9AR-V12Constitutively active androgen receptor variantTruncated androgen receptorAR-V mRNA

Inhibition of the N-terminal domain (NTD), inhibition of the DNA-binding domain (DBD), promotion of protein degradation, or inhibition of alternative mRNA splicing.