eIF4E/4E-BP ratio predicts the efficacy of mTOR targeted therapies

• Published in: Cancer research (Chicago, Ill.) Vol. 72; no. 24; pp. 6468 - 6476
• Main Authors: Alain, Tommy, Morita, Masahiro, Fonseca, Bruno D, Yanagiya, Akiko, Siddiqui, Nadeem, Bhat, Mamatha, Zammit, Domenick, Marcus, Victoria, Metrakos, Peter, Voyer, Lucie-Anne, Gandin, Valentina, Liu, Yi, Topisirovic, Ivan, Sonenberg, Nahum
• Format: Journal Article
• Language: English
• Published: United States 15.12.2012
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Adaptor Proteins, Signal Transducing - physiology; Animals; Antineoplastic Agents - therapeutic use; Biomarkers, Pharmacological - metabolism; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Biomarkers, Tumor - physiology; Cells, Cultured; Eukaryotic Initiation Factor-4E - genetics; Eukaryotic Initiation Factor-4E - metabolism; Eukaryotic Initiation Factor-4E - physiology; Gene Expression Regulation, Neoplastic - drug effects; HeLa Cells; Hep G2 Cells; Humans; Mice; Mice, Knockout; Molecular Targeted Therapy; Neoplasms - diagnosis; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; NIH 3T3 Cells; Phosphoproteins - genetics; Phosphoproteins - metabolism; Phosphoproteins - physiology; Prognosis; Protein Kinase Inhibitors - therapeutic use; TOR Serine-Threonine Kinases - antagonists & inhibitors; Treatment Outcome
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-12-2395

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.