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mTOR and cancer: insights into a complex relationship

Abstract

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.

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Figure 1: Circuitry of the mTORC1 and mTORC2 pathways and their relationships to the PI3K pathway.
Figure 2: Two models to explain the varying effects of long-term rapamycin treatment on Akt activity.

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Acknowledgements

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.

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Correspondence to David M. Sabatini.

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DATABASES

National Cancer Institute Cancer Types

breast cancers

glioblastoma

Kaposi sarcoma

leukaemia

mantle-cell lymphoma

renal-cell cancer

National Cancer Institute Drug Dictionary

CCI-779

RAD001

Rapamycin

FURTHER INFORMATION

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Information on AP23573 from Ariad Pharmaceuticals

Information on RAD001 from Novartis

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Sabatini, D. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer 6, 729–734 (2006). https://doi.org/10.1038/nrc1974

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