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.
Highlights
MTOR is a multifunctional serine/threonine kinase, which exists in 2 distinct complexes, mTOR complex 1 and 2. mTORC1 governs many cellular processes including mRNA translation, cell growth, and proliferation, by phosphorylating downstream targets such as 4E-BPs and S6Ks [1]. mTORC2 controls cell survival and cytoskeleton organization by modulating the activity of AGC kinases (e.g., Akt and SGK1) and regulates nascent polypeptide stability [2]
To ascertain that 4E-BPs are responsible for the anti-neoplastic activity of Active-site mTOR inhibitors (asTORi), we investigated the effects of PP242 on the neoplastic growth of WTE1A/Ras and E1A/Ras-transformed p53À/À/4e-bp1/2À/À mouse embryonic fibroblasts (MEF) (4E-BP DKOE1A/Ras). 4E-BP DKOE1A/Ras MEFs are devoid of all 4E-BPs, as MEFs do not express 4E-BP3 [7]
Discussion mTOR signaling is frequently dysregulated in cancer and is being targeted in clinical trials using asTORi [1, 41]
Summary
MTOR is a multifunctional serine/threonine kinase, which exists in 2 distinct complexes, mTOR complex 1 and 2 (mTORC1 and 2; ref. 1). mTORC1 governs many cellular processes including mRNA translation, cell growth, and proliferation, by phosphorylating downstream targets such as 4E-BPs and S6Ks [1]. mTORC2 controls cell survival and cytoskeleton organization by modulating the activity of AGC kinases (e.g., Akt and SGK1) and regulates nascent polypeptide stability [2]. MTOR is a multifunctional serine/threonine kinase, which exists in 2 distinct complexes, mTOR complex 1 and 2 MTORC1 governs many cellular processes including mRNA translation, cell growth, and proliferation, by phosphorylating downstream targets such as 4E-BPs and S6Ks [1]. MTORC2 controls cell survival and cytoskeleton organization by modulating the activity of AGC kinases (e.g., Akt and SGK1) and regulates nascent polypeptide stability [2]. Authors' Affiliations: Departments of 1Biochemistry, 2Anatomy and Cell Biology, and 3Oncology, 4Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, 5Goodman Cancer Research Centre, 6Division of Gastroenterology, Department of Medicine, Departments of 7Pathology and 8Surgery, Hepatopancreatobiliary and Transplant Research Unit, McGill University Health Centre, Montreal, Quebec, Canada; 9Department of Surgery, College of Medicine, King Saudi University, Riyadh, Saudi Arabia; and 10Intellikine, La Jolla, California. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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