Androgen receptor splice variant 7 (AR-V7) in castration-resistant prostate cancer: Molecular mechanisms and therapeutic strategies.

Androgen receptor splice variant 7 (AR-V7) is a principal driver of resistance to androgen receptor signaling inhibitors in castration-resistant prostate cancer. By virtue of its truncated ligand-binding domain, AR-V7 functions as a constitutively active transcription factor, sustaining oncogenic signaling independently of androgenic ligands. Its biogenesis is orchestrated by epigenetic regulators and splicing factors, including jumonji domain-containing 6 and eukaryotic translation initiation factor 4A3, which facilitate the production of stabilizing peptides such as that encoded by circSRCAP. AR-V7 establishes a distinct transcriptional programme, frequently cooperating with full-length AR and co-activators like YAP1/TAZ to activate proliferative genes (e.g., UBE2C) and repress tumor suppressors (e.g., SLC22A3). Protein stability is tightly controlled by deubiquitinases USP22 and USP14, while targeted degradation is mediated by the HSP70-STUB1 complex. Clinically, detection of AR-V7 in circulating tumor cells serves as an actionable biomarker, enabling selection of taxane chemotherapy over ineffective androgen receptor signaling inhibitors. Emerging therapeutic strategies include proteolysis-targeting chimaeras, N-terminal domain inhibitors, and agents targeting CDK9 or PRMT1. Overcoming AR-V7-mediated resistance will require deeper biological dissection using single-cell multi-omics and the development of rational combination therapies, representing a pivotal challenge in precision oncology for castration-resistant prostate cancer.