Abstract 236: Increased phosphorylation of eIF4E induces resistance to treatment with mTOR inhibitors alone or together with AR antagonists in advanced prostate cancer

The standard of care for patients with recurrent prostate cancer (PCa) is the use of androgen receptor (AR) antagonists, but the treatment ultimately fails, resulting in the development of castration resistant PCa (CRPC). Patients with CRPC are frequently continue to express an active AR, despite castration resistance, and AR inhibitors remain effective in these patients for several months. We previously showed that upregulation of mammalian target of rapamycin (mTOR) activity upon use of AR antagonists contributed to acquired resistance to this therapy, and that a combination of an mTOR inhibitor and an AR antagonist overcame resistance to AR antagonists alone (Wang et al, Oncogene, 2008;27(56):7106-17). Based on our data, a Phase II clinical trial was conducted to determine the efficacy of the combination of the mTOR inhibitor RAD001 and the AR antagonist bicalutamide in bicalutamide-naïve CRPC patients (ClinicalTrials.gov: NCT00814788). This study, which was recently concluded, showed a response rate of 75% with this combination with the historical control of 25%. The overall goal of this project was to define pathways that results in resistance to combinations of mTOR and AR inhibitors in patients with CRPC. Comparison of various mTOR inhibitors: the mTORC1 inhibitor RAD001, a mTORC1/C2 dual inhibitor INK128 and a mTORC1/C2/PI3K triple inhibitor BEZ-235 either alone or in combination with AR antagonists bicalutamide and enzalutamide in various prostate derived cell lines including C4-2, PC-346C, 22Rv1 and CWR-R1, identified cells that were resistant (CWR-R1, PC-346C) vs those that were sensitive (22Rv1, C4-2) to these inhibitors. Investigation of the base-line molecular profile of these cells demonstrated that those that expressed high levels of phosphorylated form of eIF4E (S209) were resistant to mTOR inhibitors. Downregulation of eIF4E phosphorylation by siRNA resulted in sensitivity of CRPC cells to the combination of the mTOR inhibitors with AR antagonists. Investigation of the mechanism by which eIF4E phosphorylation levels increased in certain CRPC cells but not in others revealed that expression and transcriptional activity of the AR negatively correlated with the levels of eIF4E phosphorylation. In cells with high basal levels of phospho-eIF4E, bicalutamide further increased eIF4E phosphorylation, whereas those with low eIF4E levels were not further affected. The ability of AR inhibition to suppress eIF4E phosphorylation was mediated by MAP ki