eIF4E/4E-BP Ratio Predicts the Efficacy of mTOR Targeted Therapies

Abstract

Active-site mTOR inhibitors (asTORi) hold great promise for targeting dysregulated mTOR signaling in cancer. Because of the multifaceted nature of mTORC1 signaling, identification of reliable biomarkers for the sensitivity of tumors to asTORi is imperative for their clinical implementation. Here, we show that cancer cells acquire resistance to asTORi by downregulating eukaryotic translation initiation factor (eIF4E)-binding proteins (4E-BPs-EIF4EBP1, EIF4EBP2). Loss of 4E-BPs or overexpression of eIF4E renders neoplastic growth and translation of tumor-promoting mRNAs refractory to mTOR inhibition. Conversely, moderate depletion of eIF4E augments the anti-neoplastic effects of asTORi. The anti-proliferative effect of asTORi in vitro and in vivo is therefore significantly influenced by perturbations in eIF4E/4E-BP stoichiometry, whereby an increase in the eIF4E/4E-BP ratio dramatically limits the sensitivity of cancer cells to asTORi. We propose that the eIF4E/4E-BP ratio, rather than their individual protein levels or solely their phosphorylation status, should be considered as a paramount predictive marker for forecasting the clinical therapeutic response to mTOR inhibitors. Cancer Res; 72(24); 6468-76. Ó2012 AACR.

mTOR Signaling in Growth, Metabolism, and Disease

“…on 4EBP phosphorylation, and the ratio of 4EBP to eIF4E expression correlates well with their sensitivity to mTOR inhibitors (Alain et al, 2012;She et al, 2010).…”

Dual Abrogation of Mnk and Mtor: A Novel Therapeutic Approach for the Treatment of Aggressive Cancers

“…These mRNAs include YB1, vimentin, MTA1 and CD44, all of which have a significant role in the process of metastasis. Hyperactive mTOR signaling has a profound effect on the translational landscape of cancer cells by positively regulating this four-gene invasion signature [63,83].…”

“…Chronic mTOR inhibition in SW620 colon cancer cells with superior catalytic site inhibitors such as AZD8055, resulted in an increase in eIF4E expression. This shift in signaling promotes cap-dependent translation and appears to be more instrumental in cancer progression in comparison to S6K signaling [64,75,83].…”

Regulation of global and specific mRNA translation by the mTOR signaling pathway

“…30,31 A potential explanation for this comes from findings that the level of expression of the 4E-BPs respective to eIF4E determines the response of cells to mTOR inhibitors. 25,32 Given that the ratio of eIF4E to the 4E-BPs may differ between cell types, this provides a likely explanation for the differing susceptibility of cancer cells to mTOR inhibitors. 32 Additional protein kinases have been shown to regulate phosphorylation of the 4E-BPs, including GSK3b and CK1e, 33,34 but their relevance in oncogene-and growth factor-induced protein synthesis remains unknown at the moment.…”