Androgen receptor splice variant 7 (AR-V7) (AR-V7)

Androgen receptor splice variant 7 (AR-V7) is a truncated, constitutively active isoform of the androgen receptor that lacks the C-terminal ligand-binding domain (LBD) while retaining the N-terminal transactivation domain and the DNA-binding domain. It arises from alternative splicing of the AR pre-mRNA, typically involving the inclusion of cryptic exon 3, and its expression is frequently induced by the selective pressure of androgen deprivation therapy or second-generation androgen receptor-signaling inhibitors (ARSis). Because it lacks the LBD, AR-V7 is intrinsically resistant to conventional drugs like enzalutamide and abiraterone, which rely on LBD binding or androgen depletion to inhibit receptor activity. AR-V7 localizes to the nucleus independently of ligands, where it functions as a transcription factor to drive the expression of genes associated with cell cycle progression and survival, making it a key driver of lethal castration-resistant prostate cancer (CRPC). Detection of AR-V7 in circulating tumor cells serves as a critical predictive biomarker for resistance to ARSi therapy and helps guide the transition to alternative treatments such as taxane-based chemotherapy. Current drug development efforts focus on novel strategies to bypass the missing LBD, including inhibitors of the N-terminal domain and targeted protein degraders.

Other names

AR3Androgen receptor variant 7AR-V7Truncated androgen receptor splice variant 7

Drugs targeting AR-V7 primarily act through the inhibition of the N-terminal domain (NTD) or the DNA-binding domain (DBD), as the variant lacks the C-terminal ligand-binding domain (LBD) targeted by conventional therapies. Mechanisms include direct NTD antagonism, induction of proteasomal degradation (e.g., via molecular glues or PROTACs), and inhibition of AR-V7 dimerization or DNA binding.