Androgen-Regulated Proteome Reveals A Therapeutically Relevant Androgen Receptor Coactivator Target In Prostate Cancer

Resistance to androgen deprivation therapy (ADT) and the development of castration resistant prostate cancer (CRPC) remains a major challenge in the treatment of advanced prostate cancer (PCa). Elucidation of resistance mechanisms leading to CRPC is essential to develop novel therapeutic interventions. Using a systems biology approach, we interrogated the androgen-regulated proteome and identified a mitotic Kinase as a novel androgen regulated kinase in PCa. The kinase was shown to be androgen-regulated in PCa and its nuclear localisation significantly increased in CRPC and was associated with biochemical relapse. Interestingly, the Kinase interacted directly with the amino terminus transactivation and carboxy terminus ligand binding domain of androgen receptor (AR), resulting in stabilisation of AR protein and its activity. The AR-driven global transcriptional program was regulated by this coactivator kinase including pathways involved in tumour invasion and metastasis. The inhibition of the kinase function decreased AR levels and activity, and slowed growth of PCa cell lines and human PCa explants. Thus the mitotic kinase is a novel AR-Stablised kinase with potential for clinical applications as both a candidate biomarker of PCa progression and a therapeutic target in advanced disease. Citation Format: Mohammad Asim, Charlie Massie, Anne Warren, Katarina Luko, Brinder Chohan, Suraj Menon, Ajoeb Baridi, Folake Orafidiya, Wanfeng Zhao, Carlos Escriu, Hisham Mohammed, Clive D’Santos, Xiaoping Yang, Chris Taylor, Arham Qureshi, Kate Watt, Vincent Zecchini, Luke Selth, Scott Dehm, Ian Mills, Jason Carroll, Wayne Tilley, Iain McEwan, Aria Baniahmad, David Neal. Androgen-regulated proteome reveals a therapeutically relevant androgen receptor coactivator target in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-003.