Abstract
Abstract The standard of care for patients with metastatic prostate cancer (CaP) is the use of androgen receptor (AR) antagonists, but the treatment results in the development of castration resistant prostate cancer (CRPC). 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 Identifier: NCT00814788). Our study, which was recently concluded, showed that some patients responded strongly to the combination while others were seemingly resistant. The overall goal of this project was to define pathways to overcome resistance to combinations of mTOR and AR inhibitors. Comparison of a mTORC1 inhibitor, a mTORC1/C2 dual inhibitor and a mTORC1/C2/PI3K triple inhibitor either alone or in combination with bicalutamide in various prostate derived cell lines revealed cells that were resistant vs those that were responsive to these inhibitors. Investigation of the basal molecular profile of these cell lines demonstrated that cells that expressed high levels of the phosphorylated form of eIF4E S209, a translation initiation factor activated downstream of mTOR phosphorylation, were resistant to mTOR inhibitors. Interestingly, in cells with high basal eIF4E phosphorylation, bicalutamide further increased eIF4E phosphorylation. Inhibition of eIF4E by siRNA upregulated p38MAPK activity and also increased the levels of the epidermal growth factor receptor (EGFR) and ErbB3, a member of the same family. Since p38MAPK activates the phosphorylation of Mnk1/2, which in turn phosphorylates eIF4E(S209), we investigated the effects of the Mnk inhibitor CGP57380 in prostate cancer cells. A combination of CGP57380 and the dual mTORC1/C2 inhibitor INK-128 completely eliminated cell growth in cell lines resistant to either mTOR and/or AR inhibitors, including cells that did not respond to the Mnk inhibitor by itself. Our results indicate that patients who develop resistance to anti-androgen therapy may benefit from a combination of an mTOR inhibitor in combination with an MNK inhibitor. Citation Format: Leandro S. D'Abronzo, Ryan Beggs, Swagata Bose, Paramita Ghosh. Increased phosphorylation of eIF4E induces resistance to treatment with mTOR inhibitors alone or together with AR antagonists in advanced prostate cancer. [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 1725. doi:10.1158/1538-7445.AM2014-1725
Published Version
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