Targeting mTOR signaling for cancer therapy
Introduction
Genetic mutations and compensatory changes lead to dysregulated proliferation or decreased cell death, and are implicated in the aetiology of many human malignancies. The signaling pathway composed of insulin-like growth factor-I receptor (IGFR), phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt/PKB) and mammalian target of rapamycin (mTOR), designated the IGFR–PI3K–Akt–mTOR signaling pathway, is crucial for cell growth and survival 1., 2., 3., 4.••. Dysregulation of this pathway generates a favourable oncogenic environment, and has been documented in a variety of transformed cells and human tumours 1., 5.•. Although mutations of mTOR itself have not been reported, mutations in components of mTOR-related signaling pathways have frequently been described in human malignant diseases 1., 5.•, 6.. Specifically, elevated levels and/or constitutive activation of diverse oncoproteins, such as growth factor receptors, PI3K, Akt/PKB, ribosomal p70S6 kinase (S6K1), eukaryotic initiation factor-4E (eIF4E) and cyclin D, are found in numerous human tumours. These include lymphomas, melanomas, gliomas, central nervous system malignancies, and carcinomas of the lung, bladder, kidney, ovary, breast, prostate, stomach, pancreas, head and neck 1., 5.•, 7., 8., 9.. Intriguingly, tumour cells in which IGFR–PI3K–Akt–mTOR signaling is dysregulated are more susceptible than normal cells to inhibition of mTOR. This could form a basis for mTOR inhibitors as potential tumour-selective therapeutic agents. Here, we review recent advances made in studies of mTOR signaling as a target for cancer therapy.
Section snippets
Structure of mTOR
mTOR, also named FRAP (FK506-binding protein 12 [FKBP-12]- and rapamycin-associated protein), RAFT1 (rapamycin and FKBP-12 target-1), RAPT1 (rapamycin target-1) or SEP (sirolimus effector protein), is a 289 kDa serine/threonine kinase, which was identified as the mammalian orthologue of yeast Tor in the mid-1990s 10., 11.•. The mTOR/FRAP gene maps to human chromosome 1p36.2. Despite the discovery of rapamycin as a fungicide in the 1970s, the first identification of yeast Tor (Tor1 and Tor2 in
mTOR inhibitors
Evidence increasingly implicates mTOR as a central player in cell proliferation, growth, differentiation, migration, and survival 3., 4.••, 13., 19., 34., 35., 36.. Because of the frequent dysregulation of the mTOR signaling pathway in cancer, mTOR has become a target for cancer therapy. Three potent and specific mTOR inhibitors have been reported: rapamycin, CCI-779 (also called cell-cycle inhibitor-779, rapamycin-42,2,2-bis(hydroxymethyl)-propionic acid; Wyeth-Ayerst, PA, USA) and RAD001
Conclusions
mTOR is a central regulator in a variety of cellular events, such as proliferation, growth, differentiation, migration and survival. Frequent genetic mutations or compensatory changes occur in many human cancers, resulting in aberrant gain-of-function in mTOR signaling and potentially leading to the transformed phenotype. If dysregulated mTOR signaling causes transformation, cells could become dependent on this signaling pathway for proliferation, growth, survival and metastatic potential.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
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of special interest
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of outstanding interest
Acknowledgements
This work was supported in part by USPHS awards CA77776, CA96696, CA23099 and CA28765 (Cancer Center Support Grant) from the National Cancer Institute, through a grant from Wyeth-Ayerst Company, and American-, Lebanese- and Syrian-associated Charities (ALSAC).
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