Abstract C91: Targeting enzalutamide resistance in prostate cancer.

Abstract

Abstract Prostate cancer initially responses to androgen ablation or castration, but progression to incurable castrate-resistant prostate cancer often occurs within three years. Androgen receptor pathway inhibitor Enzalutamide (ENZ) has produced promising survival gains of patients with CRPC. However, resistance to this novel therapy also rapidly occurs and novel treatment strategies are needed. We have recently developed a unique ENZ and castrate-resistant LNCaP xenograft model. To identify key regulators and active pathways in ENZ resistant cells, genome-wide gene expression analysis was performed and analyzed using systems biological approaches. We identified that forkhead box M1 (FOXM1) is one of the key upstream regulators activated in ENZ resistant prostate cancer cells. FOXM1 is overexpressed in several cancers and it is an important regulator of cancer characteristics such as cell cycle, proliferation, invasion, metastases and cancer stem cells. FOXM1 is also a critical regulator of oxidative stress and its depletion sensitises cells to oxidative stress induced apoptosis. Interestingly, we further found out that the antibiotic ionophore and oxidative stress inducer monensin that was previously identified as a cancer-specific prostate cancer inhibitor in high-throughput screening, reduces FOXM1 pathway activity and viability of ENZ resistant cells. Thus, the results suggest that inhibition of FOXM1 is a potent novel mean to impair redox control and target ENZ resistant prostate cancer cells. Taken together, our results indicated that FOMX1 activity is increased in ENZ resistant prostate cancer cells and that targeting FOXM1 is a potential means to overcome ENZ resistance in prostate cancer. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C91. Citation Format: Kirsi Ketola, Jennifer Bishop, Martin Gleave, Amina Zoubeidi. Targeting enzalutamide resistance in prostate cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C91.