Review
Targeting the mTOR signaling network in cancer

https://doi.org/10.1016/j.molmed.2007.08.001Get rights and content

The mammalian target of rapamycin (mTOR) is an unconventional protein kinase that is centrally involved in the control of cancer cell metabolism, growth and proliferation. The mTOR pathway has attracted broad scientific and clinical interest, particularly in light of the ongoing clinical cancer trials with mTOR inhibitors. The mixed clinical results to date reflect the complexity of both cancer as a disease target, and the mTOR signaling network, which contains two functionally distinct mTOR complexes, parallel regulatory pathways, and feedback loops that contribute to the variable cellular responses to the current inhibitors. In this review, we discuss the regulatory pathways that govern mTOR activity, and highlight clinical results obtained with the first generation of mTOR inhibitors to reach the oncology clinics.

Section snippets

Bugs to drugs: the path from Easter Island to the oncology clinics

Natural products have long provided unique chemical probes for biological research, as well as powerful medicinals for the treatment of various human diseases. A case in point is rapamycin, a macrolide ester produced by Streptomyces hygroscopicus, a bacterial strain originally isolated from a soil sample collected on Easter Island in the South Pacific. As a laboratory tool, rapamycin enabled the discovery of a novel and fundamentally important pathway of eukaryotic cell growth regulation. These

TOR structure and signaling complexes

TOR is a member of the phosphoinositide-3-kinase-related kinase (PIKK) family, which plays central roles in cell growth- and stress-related signaling pathways (reviewed in [2]). These unusual protein kinases are characterized by their large size (molecular masses ranging from ∼300–500 kDa) and by the expression of a carboxyl terminal kinase domain that shows significant sequence homology to the phosphoinositide 3-kinase (PI3K) catalytic domain (Figure 1a). Despite their similarity to lipid

mTORC1 at the crossroads of nutrient sensing and mitogenic signaling pathways

In yeast, TORC1 functions as a nutrient sensor, consistent with the fact that the environmental supply of metabolic precursors normally represents the rate-limiting stimulus for the growth of single-celled organisms. The situation in metazoan tissues is considerably more complex, as growth factor availability, rather than nutrient supply, is the crucial parameter that governs cell growth and proliferation under normal conditions. Hence, it is not surprising that the mTORCs in mammals evolved

mTORC2 signaling: a work in progress

In contrast to mTORC1, for which many upstream signaling inputs have been defined, relatively little is known regarding the regulatory pathways that impinge on mTORC2. The most plausible suspect at this stage is the mitogen-activated Class I PI3K pathway. If this hypothesis proves correct, then PI3K activation would stimulate bifurcating pathways that converge on AKT, one leading to PDK1 and in turn phosphorylation of Thr308, and the second mediated by mTORC2 and triggering phosphorylation of

Deregulated mTOR signaling drives tumorigenesis

Hyperactivation of the PI3K–AKT pathway is a feature of most, if not all types of cancer cells [40]. A frequent cause of deregulated PI3K signaling in human cancer is an acquired deficiency in the phosphoinositide phosphatase, PTEN (phosphatase and tensin homolog deleted on chromosome ten). Indeed, the PTEN gene is mutated or epigenetically inactivated in an extraordinarily large number of cancers, including hematopoietic malignancies and solid (epithelial-derived) carcinomas [41]. The lipid

Mechanism of action and cellular responses to mTOR inhibitors

Rapamycin as well as the rapalogs currently in clinical development are exquisitely specific inhibitors of mTORC1, thanks to a remarkable feat of microbial engineering, which endowed these drugs with the ability to interfere with mTOR signaling by interacting with a domain found in no other naturally-occurring protein. The most well documented mechanism is a two step process that involves the initial binding of rapamycin to a cytoplasmic receptor protein, FKBP12 (FK506-binding protein of 12

Molecular determinants of therapeutic responsiveness to mTOR inhibitors

The first generation of mTOR inhibitors has now entered the oncology clinic, with 126 clinical trials, involving three distinct rapalogs, either ongoing or recently completed [59]. Torisel (also known as CCI-779, Wyeth) is in clinical development in various solid tumors (e.g. renal, melanoma, endometrial, ovarian), as well as mantle cell lymphoma. Everolimus (RAD001, Novartis) is also in clinical trials for solid tumors (e.g. breast, non small-cell lung, glioblastoma, prostate, head and neck)

Future perspectives

The current knowledge base in the field of mTOR highlights several intriguing areas for the development of second and third generation mTOR inhibitors as anticancer agents (Box 3). Rapalogs, the first generation of mTOR inhibitors to enter the clinic, are allosteric rather than direct inhibitors of the mTOR kinase domain, and are selective for mTORC1. By contrast, small molecule inhibitors that target the mTOR kinase domain will suppress mTORC1 and mTORC2 functions, a feature that could

Conflicts of interest

R.T.A. is an employee of Wyeth, which is developing the rapalog, Torisel, for cancer therapy.

Acknowledgements

We thank Elizabeth Lang for critical reading of the manuscript. This work was supported by NIH grants CA76193 (to R.T.A. and G.G.C.), CA52995 (to R.T.A.) and CA101012 (to G.G.C.).

References (87)

  • H.H. Zhang

    S6K1 regulates GSK3 under conditions of mTOR-dependent feedback inhibition of Akt

    Mol. Cell

    (2006)
  • S.G. Dann

    mTOR Complex1-S6K1 signaling: at the crossroads of obesity, diabetes and cancer

    Trends Mol. Med.

    (2007)
  • X. Long

    Rheb binds and regulates the mTOR kinase

    Curr. Biol.

    (2005)
  • Y. Sancak

    PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase

    Mol. Cell

    (2007)
  • A. Hahn-Windgassen

    Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity

    J. Biol. Chem.

    (2005)
  • K.S. Kovacina

    Identification of a proline-rich Akt substrate as a 14-3-3 binding partner

    J. Biol. Chem.

    (2003)
  • N. Oshiro

    The proline-rich Akt substrate of 40 kDa (PRAS40) is a physiological substrate of mammalian target of rapamycin complex 1

    J. Biol. Chem.

    (2007)
  • B.D. Fonseca

    PRAS40 is a target for mammalian target of rapamycin complex 1 and is required for signaling downstream of this complex

    J. Biol. Chem.

    (2007)
  • L. Wang

    PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding

    J. Biol. Chem.

    (2007)
  • S.S. Schalm et al.

    Identification of a conserved motif required for mTOR signaling

    Curr. Biol.

    (2002)
  • S.S. Schalm

    TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function

    Curr. Biol.

    (2003)
  • H. Nojima

    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.

    (2003)
  • M.P. Byfield

    hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase

    J. Biol. Chem.

    (2005)
  • E.M. Smith

    The tuberous sclerosis protein TSC2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain cellular stresses

    J. Biol. Chem.

    (2005)
  • J. Luo

    Targeting the PI3K-Akt pathway in human cancer: rationale and promise

    Cancer Cell

    (2003)
  • O.J. Shah

    Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies

    Curr. Biol.

    (2004)
  • J.E. Skeen

    Akt deficiency impairs normal cell proliferation and suppresses oncogenesis in a p53-independent and mTORC1-dependent manner

    Cancer Cell

    (2006)
  • Q.W. Fan

    A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma

    Cancer Cell

    (2006)
  • D.D. Sarbassov

    Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB

    Mol. Cell

    (2006)
  • J.P. Baak

    Lack of PTEN expression in endometrial intraepithelial neoplasia is correlated with cancer progression

    Hum. Pathol.

    (2005)
  • Z.A. Knight

    A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling

    Cell

    (2006)
  • J. Brugarolas et al.

    Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes

    Cancer Cell

    (2004)
  • T.L. Phung

    Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin

    Cancer Cell

    (2006)
  • D.M. Sabatini

    mTOR and cancer: insights into a complex relationship

    Nat. Rev. Cancer

    (2006)
  • D.D. Sarbassov

    Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex

    Science

    (2005)
  • D.R. Plas et al.

    Akt-dependent transformation: there is more to growth than just surviving

    Oncogene

    (2005)
  • E. Jacinto

    Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive

    Nat. Cell Biol.

    (2004)
  • D.D. Sarbassov

    Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton

    Curr. Biol.

    (2004)
  • Y.G. Gangloff

    Disruption of the mouse mTOR gene leads to early postimplantation lethality and prohibits embryonic stem cell development

    Mol. Cell. Biol.

    (2004)
  • M. Murakami

    mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells

    Mol. Cell. Biol.

    (2004)
  • Q. Yang

    Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity

    Genes Dev.

    (2006)
  • Z. Zeng

    Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML

    Blood

    (2006)
  • J. Dong et al.

    Tsc2 is not a critical target of Akt during normal Drosophila development

    Genes Dev.

    (2004)
  • Cited by (307)

    View all citing articles on Scopus
    View full text