Targeting mTOR signaling for cancer therapy

https://doi.org/10.1016/S1471-4892(03)00071-7Get rights and content

Abstract

The mammalian target of rapamycin (mTOR), an atypical serine/threonine kinase, plays a central role in the regulation of cell proliferation, growth, differentiation, migration and survival. Dysregulation of mTOR signaling occurs in diverse human tumours, and can confer higher susceptibility to inhibitors of mTOR. Rapamycin and its derivatives, CCI-779 and RAD001 (designated rapamycins), specifically inhibit the function of mTOR, leading to inactivation of ribosomal S6K1 and inhibition of cap-dependent translation initiation through the 4E–BP1/eIF4E pathway. The overall effect is an accumulation of cells in the G1 phase of the cell-cycle, and potential apoptosis. Preclinical studies indicate that rapamycins are potent inhibitors of the proliferation of numerous tumour cell lines in culture and of murine syngeneic tumour models or human xenografts. RAD001 and CCI-779 are in phase I and II trials, respectively, as anti-cancer agents. These trials have demonstrated promising anti-cancer activity and relatively mild side effects of CCI-779. Emerging results suggest that inhibition of mTOR signaling can be exploited as a potential tumour-selective therapeutic strategy.

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:

  • of special interest

  • ••

    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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