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Sci. Signal., 21 April 2009
Vol. 2, Issue 67, p. pe24
[DOI: 10.1126/scisignal.267pe24]


The Pharmacology of mTOR Inhibition

David A. Guertin1 and David M. Sabatini1,2,3*

1 Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02141, USA.
2 Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
3 Koch Center for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.

Abstract: A flurry of reports indicates that we are entering a new phase in the development of mammalian target of rapamycin (mTOR)–based therapies for oncology. Here, we summarize exciting findings regarding mTOR signaling and the outlook for mTOR inhibitors as tools to study the mTOR pathway and as drugs in the clinic.

* Corresponding author. Telephone, 617-258-6407; e-mail, sabatini{at}

Citation: D. A. Guertin, D. M. Sabatini, The Pharmacology of mTOR Inhibition. Sci. Signal. 2, pe24 (2009).

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Ann Rheum Dis 71, 575-581
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Inhibition of MTOR Disrupts Autophagic Flux in Podocytes.
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J. Am. Soc. Nephrol. 23, 412-420
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From Node to Pathway Blockade: Lessons Learned From Targeting Mammalian Target of Rapamycin.
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J. Clin. Oncol. 30, 85-87
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J. Pharmacol. Exp. Ther. 339, 421-429
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Oncogenic EGFR Signaling Activates an mTORC2-NF-{kappa}B Pathway That Promotes Chemotherapy Resistance.
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Blood 118, 3129-3136
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Cancer Discovery 1, 203-204
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mTOR Kinase Domain Phosphorylation Promotes mTORC1 Signaling, Cell Growth, and Cell Cycle Progression.
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mTORC2 Is Required for Proliferation and Survival of TSC2-Null Cells.
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Mol. Cell. Biol. 31, 2484-2498
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Phosphoproteomic Analysis Identifies Grb10 as an mTORC1 Substrate That Negatively Regulates Insulin Signaling.
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Utility of mTOR Inhibition in Hematologic Malignancies.
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Oncologist 16, 730-741
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Engineering the ABA Plant Stress Pathway for Regulation of Induced Proximity.
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Pushing the Envelope in the mTOR Pathway: The Second Generation of Inhibitors.
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Mol. Cancer Ther. 10, 395-403
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mTOR-Dependent Regulation of PHLPP Expression Controls the Rapamycin Sensitivity in Cancer Cells.
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J. Biol. Chem. 286, 6510-6520
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Reversing chemoresistance by small molecule inhibition of the translation initiation complex eIF4F.
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PNAS 108, 1046-1051
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New Strategies in the Molecular Targeting of Glioblastoma: How Do You Hit a Moving Target?.
T. F. Cloughesy and P. S. Mischel (2011)
Clin. Cancer Res. 17, 6-11
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AP-1 Regulates Cyclin D1 and c-MYC Transcription in an AKT-Dependent Manner in Response to mTOR Inhibition: Role of AIP4/Itch-Mediated JUNB Degradation.
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Mol. Cancer Res. 9, 115-130
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Target of Rapamycin Signaling in Leukemia and Lymphoma.
C. Vu and D. A. Fruman (2010)
Clin. Cancer Res. 16, 5374-5380
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Regulation of Mammalian Autophagy in Physiology and Pathophysiology.
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Mammalian Target of Rapamycin (mTOR): Conducting the Cellular Signaling Symphony.
K. G. Foster and D. C. Fingar (2010)
J. Biol. Chem. 285, 14071-14077
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mTOR Ser-2481 Autophosphorylation Monitors mTORC-specific Catalytic Activity and Clarifies Rapamycin Mechanism of Action.
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The PI3K Pathway As Drug Target in Human Cancer.
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Regulation of mTOR Complex 1 (mTORC1) by Raptor Ser863 and Multisite Phosphorylation.
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J. Biol. Chem. 285, 80-94
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Targeted Inhibition of Mammalian Target of Rapamycin Signaling Inhibits Tumorigenesis of Colorectal Cancer.
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Ribosomal Protein S6 Kinase 1 Signaling Regulates Mammalian Life Span.
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Site-Specific mTOR Phosphorylation Promotes mTORC1-Mediated Signaling and Cell Growth.
H. A. Acosta-Jaquez, J. A. Keller, K. G. Foster, B. Ekim, G. A. Soliman, E. P. Feener, B. A. Ballif, and D. C. Fingar (2009)
Mol. Cell. Biol. 29, 4308-4324
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Striking the balance between PTEN and PDK1: it all depends on the cell context.
A. Iwanami, T. F. Cloughesy, and P. S. Mischel (2009)
Genes & Dev. 23, 1699-1704
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Thwarting Dyskinesia by Targeting mTORC1.
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Science Signaling 2, pe42
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Science Signaling 2, pc8
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