Trends in Molecular Medicine
ReviewTargeting the mTOR signaling network in cancer
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.).
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