Abstract 676: Inhibition of FOXM1 targets both high and low PSA expressing prostate cancer cells resistant to Enzalutamide
Authors: Ketola Kirsi , Bishop Jennifer , Nip Ka Mun , Kim Soojin , Ladan Fazli , Gleave Martin , Zoubeidi Amina 
Published: May 2015

Advances in castrate-resistant prostate cancer (CRPC) treatment using androgen receptor (AR) targeted therapies have produced striking survival advantages in clinical studies; recently approved AR inhibitor Enzalutamide (ENZ) prolongs survival of patients with incurable CRPC. Although enthusiasm for this approach remains high, prostate tumor heterogeneity and the inevitable development of resistance as seen currently in the clinic and in our pre-clinical model, dictates a critical need for a better understanding of the mechanisms of resistance. We have recently developed a unique model of LNCaP-CRPC-ENZ-resistance and found that cell lines derived from serially passaged ENZ resistant tumors express different levels of prostate specific antigen (PSA). Especially low PSA expressing cells are believed to be highly enriched with cancer stem cells with high self-renewal and these cells have been considered difficult to target with current therapies.

To define molecular mechanisms contributing to treatment resistance in an unbiased manner, we performed gene profiling on LNCaP, CRPC and ENZ resistant cell lines expressing low and high levels of PSA. Using systems biological approaches, we found that several genes and pathways involved in stem cell maintenance were altered in Enzalutamide resistant cells. Interestingly, forkhead box M1 (FOXM1) was one of the key pathways potentially maintaining cancer stem cells and driving dedifferentiation during ENZ resistance. FOXM1 is a transcription factor that confers treatment resistance and is required for maintenance of pluripotency in stem cells and PCa CSC-like spheroid formation as well as induction of epithelial-to-mesenchymal transition and invasion. Interestingly, FOXM1 and its downstream targets were upregulated in both PSA high and low expressing ENZ resistant cells compared to CRPC cells and correlated with poor survival and Gleason score in CRPC. In addition, mining public data, we found that FOXM1 is highly expressed in prostate cancer cells with low PSA expression, indicating that also low PSA expressing prostate cancer stem cells could be targeted by inhibiting FOXM1.

Using systems biological approaches, we further found out that the antibiotic ionophore and oxidative stress inducer Monensin, reduces FOXM1 pathway activity in ENZ resistant cells. The validation results indicated that Monensin reduced cell viability, FOXM1 transcriptional activity as well as FOXM1 protein, gene and its target gene expressions in both PSA high and low expressing ENZ resistant prostate cancer cells. Taken together, the results suggest that inhibition of FOXM1 by Monensin is a potent novel mean to target ENZ resistant cells including low PSA expressing prostate cancer stem cell-like cells.

Citation Format: Kirsi Ketola, Jennifer Bishop, Ka Mun Nip, Soojin Kim, Fazli Ladan, Martin Gleave, Amina Zoubeidi. Inhibition of FOXM1 targets both high and low PSA expressing prostate cancer cells resistant to Enzalutamide. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 676. doi:10.1158/1538-7445.AM2014-676