Androgen receptor (AR) mRNA and splice variants (AR mRNA)

The androgen receptor (AR) mRNA and its truncated splice variants, such as AR-V7 and AR-V567es, are pivotal drivers of progression in advanced prostate cancer (Lu et al., 2015, Gene). While traditional therapies target the ligand-binding domain of the AR protein, splice variants often lack this domain, resulting in constitutive, androgen-independent transcriptional activity (Antonarakis et al., 2014, N Engl J Med). This structural alteration renders conventional anti-androgens ineffective, leading to the development of castration-resistant prostate cancer (CRPC). Targeting the AR mRNA directly using antisense oligonucleotides (ASOs) or RNA interference (RNAi) allows for the simultaneous knockdown of both full-length AR and its various splice variants (Rice et al., 2016, Clin Cancer Res). This approach aims to bypass the resistance mechanisms inherent in protein-level inhibition. Clinical development has focused on agents like AZD5312, which utilize RNase H-mediated degradation of the AR transcript to reduce total AR protein levels. Monitoring AR-V7 levels in circulating tumor cells has also emerged as a critical biomarker for predicting poor response to standard hormonal therapies (Antonarakis et al., 2014, N Engl J Med). Overall, targeting the mRNA precursor provides a comprehensive strategy to inhibit AR signaling in the face of complex splicing-mediated resistance.

Other names

AR-V7AR-V567esAR transcriptNR3C4 mRNAAndrogen receptor splice variantsAR-V1AR-V3AR-V9

Antisense oligonucleotide-mediated degradation of mRNA transcripts via RNase H recruitment or RNA interference, preventing the translation of both full-length and truncated androgen receptor proteins (Rice et al., 2016, Clin Cancer Res).