Androgen receptor phosphorylation at serine 81 and serine 213 in castrate-resistant prostate cancer

Despite increases in diagnostics and effective treatments, over 300,000 men die from prostate cancer highlighting the need for specific and differentiating biomarkers. AR phosphorylation associates with castrate-resistance, with pAR^ser213 promoting transcriptional activity. We hypothesise that combined pAR^ser81 and pAR^ser213 reduces survival and would benefit from dual-targeting androgen-dependent and Akt-driven disease.

Immunohistochemistry and immunofluorescence were performed on matched hormone-naive and castrate-resistant prostate cancer samples. TempO-Seq gene profiling was analysed using DESeq2 package. LNCaP-AI cells were stimulated with DHT or EGF. WST-1 assays were performed to determine effects of Enzalutamide and BKM120 on cell viability.

Following the development of castrate-resistance, pAR^ser81 expression reduced and pAR^ser213 expression increased. Castrate-resistance pAR^ser81 expression was not associated with survival but high pAR^ser213 expression was associated with reduced survival from relapse. Combined high pAR^ser81 and pAR^ser213 was associated with reduced survival from relapse. pAR^ser81 expression was induced by 10 nM DHT or 10 nM EGF and pAR^ser213 expression was induced by treatment with 10 nM EGF in LNCaP-AI cells. Cell viability was reduced following treatment with 10 nM Enzalutamide and 10 nM BKM120. Eight genes were differentially expressed between hormone-naive and castrate-resistant tumours and twenty-five genes were differentially expressed between castrate-resistant tumours with high and low pAR^ser213 expression.

Combined pAR^ser81 and pAR^ser213 provides a novel prognostic biomarker for castrate-resistant disease and a potential predictive and therapeutic target for prostate cancer. Further studies will be required to investigate the combined effects of targeting AR and PI3K/AKT signalling.