Abstract B22: Increased phosphorylation of eIF4E induces resistance to treatment with mTOR inhibitors together with AR antagonists in advanced prostate cancer

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Abstract The anti-androgen bicalutamide is widely used in the treatment of advanced prostate cancer (CaP) in many countries, but its effect on castration resistant CaP (CRPC) is limited. We previously showed that resistance to bicalutamide results from increased activation of the mechanistic target of rapamycin (mTOR); indicating a role for mTOR inhibitors in CaP treatment. Interestingly, a clinical trial testing combinations of the mTOR inhibitor RAD001 with bicalutamide were initially effective (PSA decline>50%) in 62.5% CRPC patients, but many initial responders later developed resistance. Here we investigate causes for their difference in response. Evaluation of various CRPC cell lines identified resistant vs sensitive in vitro models, and revealed that increased eIF4E phosphorylation at S209 is associated with resistance to the combination. To recognize potential causes of resistance, we demonstrated using a human tumor xenograft mouse model, that bicalutamide use is associated with an increase in eIF4E(S209) phosphorylation. Investigations revealed that AR suppressed eIF4E phosphorylation, while the use of anti-androgens relieved this suppression, thereby triggering its increase. Additional investigation on the consequences of increased eIF4E phosphorylation in human prostatectomy samples revealed that increased eIF4E phosphorylation strongly correlated with the cell proliferation marker Ki67, indicating a role for eIF4E in tumor growth. Inhibition of eIF4E phosphorylation by siRNA suppression or treatment with CGP57380 (an inhibitor of MAPK interacting serine-threonine kinases Mnk1/2, the eIF4E upstream kinase,) sensitized CRPC cells to RAD001+bicalutamide, while eIF4E overexpression induced resistance. Our results demonstrate that bicalutamide treatment induced an increase in eIF4E phosphorylation by inhibition of AR which otherwise suppressed this phosphorylation. Increased eIF4E phosphorylation then induced resistance to the combination of anti-androgens with mTOR inhibitors by increasing proliferation. These results also indicate that resistance to RAD001+bicalutamide can be prevented by the concurrent use of a Mnk1/2 inhibitor. Citation Format: Leandro S. D'Abronzo, Michael Crapuchettes, Ryan Beggs, Ruth Vinall, Clifford Tepper, Salma Siddiqui, Maria Mudryj, Frank Melgoza, Blythe Durbin-Johnson, Ralph deVere White, Paramita Ghosh. Increased phosphorylation of eIF4E induces resistance to treatment with mTOR inhibitors together with AR antagonists in advanced prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr B22.