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

Background: 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 promoting transcriptional activity. We hypothesise that combined pAR and pAR reduces survival and would benefit from dual-targeting androgen-dependent and Akt-driven disease.

Methods: 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.

Results: Following the development of castrate-resistance, pAR expression reduced and pAR expression increased. Castrate-resistance pAR expression was not associated with survival but high pAR expression was associated with reduced survival from relapse. Combined high pAR and pAR was associated with reduced survival from relapse. pAR expression was induced by 10 nM DHT or 10 nM EGF and pAR 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 expression.

Conclusion: Combined pAR and pAR 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.