mTOR (mammalian target of rapamycin) has come a long way since its humble beginnings as a kinase of unknown function. As part of the mTORC1 and mTORC2 complexes mTOR has key roles in several pathways that are involved in human cancer, stimulating interest in mTOR inhibitors and placing it on the radar of the pharmaceutical industry. Here, I discuss the rationale for the use of drugs that target mTOR, the unexpectedly complex mechanism of action of existing mTOR inhibitors and the potential benefits of developing drugs that function through different mechanisms. The purpose is not to cover all aspects of mTOR history and signalling, but rather to foster discussion by presenting some occasionally provocative ideas.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Sarbassov, D. D., Ali, S. M. & Sabatini, D. M. Growing roles for the mTOR pathway. Curr. Opin. Cell Biol. 17, 596–603 (2005).
Tapon, N., Ito, N., Dickson, B. J., Treisman, J. E. & Hariharan, I. K. The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell 105, 345–355 (2001).
Gao, X. et al. Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nature Cell Biol. 4, 699–704. (2002).
Saucedo, L. J. et al. Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nature Cell Biol. 5, 566–571 (2003).
Stocker, H. et al. Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nature Cell Biol. 5, 559–565 (2003).
Zhang, Y. et al. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nature Cell Biol. 5, 578–581 (2003).
Tee, A. R., Manning, B. D., Roux, P. P., Cantley, L. C. & Blenis, J. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr. Biol. 13, 1259–1268 (2003).
Garami, A. et al. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol. Cell 11, 1457–1466 (2003).
Long, X., Lin, Y., Ortiz-Vega, S., Yonezawa, K. & Avruch, J. Rheb binds and regulates the mTOR kinase. Curr. Biol 15, 702–713 (2005).
Inoki, K., Li, Y., Zhu, T., Wu, J. & Guan, K. L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nature Cell Biol. 4, 648–657 (2002).
Potter, C. J., Pedraza, L. G. & Xu, T. Akt regulates growth by directly phosphorylating Tsc2. Nature Cell Biol. 4, 658–665. (2002).
Manning, B. D., Tee, A. R., Logsdon, M. N., Blenis, J. & Cantley, L. C. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol. Cell 10, 151–162 (2002).
Tee, A. R., Anjum, R. & Blenis, J. Inactivation of the tuberous sclerosis complex-1 and -2 gene products occurs by phosphoinositide 3-kinase/Akt-dependent and -independent phosphorylation of tuberin. J. Biol. Chem. 278, 37288–37296 (2003).
Johannessen, C. M. et al. The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc. Natl Acad. Sci. USA 102, 8573–8578 (2005).
Feng, Z., Zhang, H., Levine, A. J. & Jin, S. The coordinate regulation of the p53 and mTOR pathways in cells. Proc. Natl Acad. Sci. USA 102, 8204–8209 (2005).
Shaw, R. J. et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6, 91–99 (2004).
Corradetti, M. N., Inoki, K., Bardeesy, N., DePinho, R. A. & Guan, K. L. Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz–Jeghers syndrome. Genes Dev. 18, 1533–1538 (2004).
Inoki, K., Zhu, T. & Guan, K. L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577–590 (2003).
Hay, N. & Sonenberg, N. Upstream and downstream of mTOR. Genes Dev. 18, 1926–1945 (2004).
Takano, A. et al. Mammalian target of rapamycin pathway regulates insulin signaling via subcellular redistribution of insulin receptor substrate 1 and integrates nutritional signals and metabolic signals of insulin. Mol. Cell. Biol. 21, 5050–5062 (2001).
Tremblay, F. & Marette, A. Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mechanism leading to insulin resistance in skeletal muscle cells. J. Biol. Chem. 276, 38052–38060 (2001).
Haruta, T. et al. A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1. Mol. Endocrinol. 14, 783–794 (2000).
Harrington, L. S. et al. The TSC1–2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J. Cell Biol. 166, 213–223 (2004).
Shah, O. J., Wang, Z. & Hunter, T. Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr. Biol. 14, 1650–1656 (2004).
Ma, L. et al. Genetic analysis of Pten and Tsc2 functional interactions in the mouse reveals asymmetrical haploinsufficiency in tumor suppression. Genes Dev. 19, 1779–1786 (2005).
Manning, B. D. et al. Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2. Genes Dev. 19, 1773–1778 (2005).
Sarbassov, D. D., Guertin, D. A., Ali, S. M. & Sabatini, D. M. Phosphorylation and regulation of Akt/PKB by the rictor–mTOR complex. Science 307, 1098–1101 (2005).
Hresko, R. C. & Mueckler, M. mTOR/RICTOR is the Ser473 kinase for Akt/PKB in 3T3-L1 adipocytes. J. Biol. Chem. 280, 40406–40416 (2005).
Sarbassov, D. D. et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14, 1296–1302 (2004).
Jacinto, E. et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nature Cell Biol. 6, 1122–1128 (2004).
Kim, D.-H. et al. mTOR interacts with Raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163–175 (2002).
Hara, K. et al. Raptor, a binding partner of Target of Rapamycin (TOR), mediates TOR action. Cell 110, 177–189 (2002).
Schalm, S. S., Fingar, D. C., Sabatini, D. M. & Blenis, J. TOS Motif-mediated Raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr. Biol. 13, 797–806 (2003).
Nojima, H. et al. The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif. J. Biol. Chem. 278, 15461–15464 (2003).
Guertin, D. A. & Sabatini, D. M. An expanding role for mTOR in cancer. Trends Mol. Med. 11, 353–361 (2005).
Sarbassov, D. D. et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 22, 159–168 (2006).
Frias, M. A. et al. mSin1 is necessary for Akt/PKB phosphorylation and its isoforms define three distinct mTORC2s. Curr. Biol. (in the press).
Jiang, X. & Yeung, R. S. Regulation of microtubule-dependent protein transport by the TSC2/mammalian target of rapamycin pathway. Cancer Res. 66, 5258–5269 (2006).
Teachey, D. T. et al. The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL. Blood 107, 1149–1155 (2006).
Avellino, R. et al. Rapamycin stimulates apoptosis of childhood acute lymphoblastic leukemia cells. Blood 106, 1400–1406 (2005).
Thimmaiah, K. N. et al. Insulin-like growth factor I-mediated protection from rapamycin-induced apoptosis is independent of Ras-Erk1-Erk2 and phosphatidylinositol 3-kinase–Akt signaling pathways. Cancer Res. 63, 364–374 (2003).
Treeck, O., Wackwitz, B., Haus, U. & Ortmann, O. Effects of a combined treatment with mTOR inhibitor RAD001 and tamoxifen in vitro on growth and apoptosis of human cancer cells. Gynecol. Oncol. 102 292–299 (2006).
Beuvink, I. et al. The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell 120, 747–759 (2005).
Hahn, M. et al. Rapamycin and UCN-01 synergistically induce apoptosis in human leukemia cells through a process that is regulated by the Raf-1/MEK/ERK, Akt, and JNK signal transduction pathways. Mol. Cancer Ther. 4, 457–470 (2005).
Fumarola, C., La Monica, S., Alfieri, R. R., Borra, E. & Guidotti, G. G. Cell size reduction induced by inhibition of the mTOR/S6K-signaling pathway protects Jurkat cells from apoptosis. Cell Death Differ. 12, 1344–1357 (2005).
Galanis, E. et al. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J. Clin. Oncol. 23, 5294–5304 (2005).
Chang, S. M. et al. Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest. New Drugs 23, 357–361 (2005).
Atkins, M. B. et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J. Clin. Oncol. 22, 909–918 (2004).
Witzig, T. E. et al. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J. Clin. Oncol. 23, 5347–5356 (2005).
Franz, D. N. et al. Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann. Neurol. 59, 490–498 (2006).
Hengstschlager, M., Rosner, M., Fountoulakis, M. & Lubec, G. Tuberous sclerosis genes regulate cellular 14–3–3 protein levels. Biochem. Biophys. Res. Commun. 312, 676–683 (2003).
Lamb, R. F. et al. The TSC1 tumour suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho. Nature Cell Biol. 2, 281–287 (2000).
Yuan, J. et al. Identification and characterization of RHEBL1, a novel member of Ras family, which activates transcriptional activities of NF-kB. Mol. Biol. Rep. 32, 205–214 (2005).
Saito, K., Araki, Y., Kontani, K., Nishina, H. & Katada, T. Novel role of the small GTPase Rheb: its implication in endocytic pathway independent of the activation of mammalian target of rapamycin. J. Biochem. 137, 423–430 (2005).
Karbowniczek, M. et al. Regulation of B-Raf kinase activity by tuberin and Rheb is mammalian target of rapamycin (mTOR)-independent. J. Biol. Chem. 279, 29930–29937 (2004).
Yee, W. M. & Worley, P. F. Rheb interacts with Raf-1 kinase and may function to integrate growth factor- and protein kinase A-dependent signals. Mol. Cell. Biol. 17, 921–933 (1997).
Karbowniczek, M., Robertson, G. P. & Henske, E. P. Rheb inhibits C-Raf activity and B-Raf/C-Raf heterodimerization. J. Biol. Chem. 27 Jun 2006 (doi:10.1074/jbc.M605273200).
Tavazoie, S. F., Alvarez, V. A., Ridenour, D. A., Kwiatkowski, D. J. & Sabatini, B. L. Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nature Neurosci. 8, 1727–1734 (2005).
Kaper, F., Dornhoefer, N. & Giaccia, A. J. Mutations in the PI3K/PTEN/TSC2 pathway contribute to mammalian target of rapamycin activity and increased translation under hypoxic conditions. Cancer Res. 66, 1561–1569 (2006).
Neshat, M. S. et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc. Natl Acad. Sci. USA 98, 10314–10319 (2001).
Podsypanina, K. et al. An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/− mice. Proc. Natl Acad. Sci. USA 98, 10320–10325 (2001).
Majumder, P. K. et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nature Med. 10, 594–601 (2004).
Wendel, H. G. et al. Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 428, 332–337 (2004).
Chan, S. et al. Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J. Clin. Oncol. 23, 5314–5322 (2005).
Sun, S. Y. et al. Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res. 65, 7052–7058 (2005).
O'Reilly, K. E. et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 66, 1500–1508 (2006).
Fan, Q. W. et al. A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 9, 341–349 (2006).
Knight, Z. A. et al. A pharmacological map of the PI3-K-family defines a role for p110α in insulin signaling. Cell 125, 733–747 (2006).
Foukas, L. C. et al. Critical role for the p110α phosphoinositide-3-OH kinase in growth and metabolic regulation. Nature 441, 366–370 (2006).
Guba, M. et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nature Med. 8, 128–135 (2002).
Campistol, J. M., Gutierrez-Dalmau, A. & Torregrosa, J. V. Conversion to sirolimus: a successful treatment for posttransplantation Kaposi's sarcoma. Transplantation 77, 760–762 (2004).
Stallone, G. et al. Sirolimus for Kaposi's sarcoma in renal-transplant recipients. N. Engl. J. Med. 352, 1317–1323 (2005).
Aoki, Y. & Tosato, G. Targeted inhibition of angiogenic factors in AIDS-related disorders. Curr. Drug Targets Infect. Disord. 3, 115–128 (2003).
Phung, T. L. et al. Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin. Cancer Cell (in the press).
Hudson, C. C. et al. Regulation of hypoxia-inducible factor 1α expression and function by the mammalian target of rapamycin. Mol. Cell. Biol. 22, 7004–7014 (2002).
Del Bufalo, D. et al. Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus. Cancer Res. 66, 5549–5554 (2006).
Thomas, G. V. et al. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nature Med. 12, 122–127 (2006).
Bruns, C. J. et al. Rapamycin-induced endothelial cell death and tumor vessel thrombosis potentiate cytotoxic therapy against pancreatic cancer. Clin. Cancer Res. 10, 2109–2119 (2004).
Shiojima, I. & Walsh, K. Role of Akt signaling in vascular homeostasis and angiogenesis. Circ. Res. 90, 1243–1250 (2002).
Montaner, S. et al. Endothelial infection with KSHV genes in vivo reveals that vGPCR initiates Kaposi's sarcomagenesis and can promote the tumorigenic potential of viral latent genes. Cancer Cell 3, 23–36 (2003).
Williams, M. E. & Densmore, J. J. Biology and therapy of mantle cell lymphoma. Curr. Opin. Oncol. 17, 425–431 (2005).
Muise-Helmericks, R. C. et al. Cyclin D expression is controlled post-transcriptionally via a phosphatidylinositol 3-kinase/Akt-dependent pathway. J. Biol. Chem. 273, 29864–29872 (1998).
Gao, N. et al. G1 cell cycle progression and the expression of G1 cyclins are regulated by PI3K/AKT/mTOR/p70S6K1 signaling in human ovarian cancer cells. Am. J. Physiol. Cell. Physiol. 287, C281–C291 (2004).
Law, M. et al. Rapamycin disrupts cyclin/cyclin-dependent kinase/p21/proliferating cell nuclear antigen complexes and cyclin D1 reverses rapamycin action by stabilizing these complexes. Cancer Res. 66, 1070–1080 (2006).
Albers, M. W. et al. FKBP-rapamycin inhibits a cyclin-dependent kinase activity and a cyclin D1–Cdk association in early G1 of an osteosarcoma cell line. J. Biol. Chem. 268, 22825–22829 (1993).
Hashemolhosseini, S. et al. Rapamycin inhibition of the G1 to S transition is mediated by effects on cyclin D1 mRNA and protein stability. J. Biol. Chem. 273, 14424–14429 (1998).
Hipp, S. et al. Inhibition of the mammalian target of rapamycin and the induction of cell cycle arrest in mantle cell lymphoma cells. Haematologica 90, 1433–1434 (2005).
Rudelius, M. et al. Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphoma. Blood 27 Apr 2006 (doi:10.1182/blood-2006-04-015586).
Gangloff, Y. G. et al. Disruption of the mouse mTOR gene leads to early postimplantation lethality and prohibits embryonic stem cell development. Mol. Cell. Biol. 24, 9508–9516 (2004).
Murakami, M. et al. mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells. Mol. Cell. Biol. 24, 6710–6718 (2004).
Eng, C. P., Sehgal, S. N. & Vezina, C. Activity of rapamycin (AY-22, 989) against transplanted tumors. J. Antibiot. 37, 1231–1237 (1984).
Kim, D. H. et al. GβL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol. Cell 11, 895–904 (2003).
Loewith, R. et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol. Cell 10, 457–468 (2002).
I gratefully acknowledge former and current members of the lab who have contributed to the results described and the US National Institutes of Health, the Whitehead Institute, the Pew Charitable Trusts and the Rita Allen Foundation for support of our work on the mTOR pathway.
The author declares no competing financial interests.
National Cancer Institute Cancer Types
National Cancer Institute Drug Dictionary
About this article
Cite this article
Sabatini, D. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer 6, 729–734 (2006). https://doi.org/10.1038/nrc1974
PTEN Blocking Stimulates Corticospinal and Raphespinal Axonal Regeneration and Promotes Functional Recovery After Spinal Cord Injury
Journal of Neuropathology & Experimental Neurology (2021)
Cell Cycle (2021)
Frontiers in Immunology (2021)
Molecular Therapy - Oncolytics (2021)