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  • Review Article
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The tor pathway: a target for cancer therapy

Nature Reviews Cancer volume 4, pages 335–348 (2004)Cite this article

Key Points

  • Target of rapamycin (TOR) — an essential protein that is conserved in eukaryotes — directly or indirectly regulates the translation of ribosomal proteins and, in yeast, regulates ribosome biogenesis.

  • TOR controls cap-dependent translation initiation through phosphorylating and inactivating eukaryotic initiation factor 4E binding proteins, which allows formation of the eIF4F complex that is required for translation initiation of mRNAs that have long structured 5′-untranslated regions.

  • TOR functions as a sensor of mitogen, energy and nutritient levels, acting as a gatekeeper for cell-cycle progression from G1 to S phase.

  • Pathways that regulate TOR signalling are complex and involve positive regulators such as AKT that phosphorylate and inactivate negative regulators such as tuberin (TSC2).

  • Pathways upstream of TOR are frequently activated in cancer. This can be through increased activity of phosphatidylinositol-3-kinase–AKT or kinases that regulate TSC2, or through mutations that inactivate TSC proteins.

  • The TOR pathway is also upregulated in many human cancers and oncogenic transformation might sensitize cells to TOR inhibitors. TOR therefore represents a novel therapeutic target.

  • Rapamycin and its analogues are highly specific inhibitors of TOR and are now in Phase I–III oncology clinical trials.

Abstract

Rapamycin, a macrocyclic lactone, is a highly specific inhibitor of the serine/threonine protein kinase target of rapamycin (TOR). Although it is clear that TOR controls initiation of protein translation, recent results indicate that TOR is a central controller, integrating a plethora of signalling pathways that respond to growth factors and nutritional status. In addition to the role of rapamycin as an immune suppressant, emerging data indicate that genetic and metabolic changes accompanying malignant transformation might cause hypersensitivity to TOR inhibition.

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Figure 1: Target of rapamycin is a central regulator of cell growth and proliferation in response to environmental and nutritional conditions.
Figure 2: Domain structure of target of rapamycin.
Figure 3: Regulation of target of rapamycin signalling by raptor.
Figure 4: The target of rapamycin signalling pathway.
Figure 5: Rapamycin can induce apoptosis.
Figure 6: Increased expression of eIF4E is implicated in transformation.

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Acknowledgements

The authors are supported by grants from the United States Public Health Service and the American, Lebanese, Syrian Associated Charities.

Correction: The DOI number given for this article in the May 2004 print issue of Nature Reviews Cancer was wrong. The correct DOI number is: doi:10.1038/nrc1362.

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Authors and Affiliations

  1. Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, 38105, Tennessee, USA

    Mary-Ann Bjornsti & Peter J. Houghton

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  1. Mary-Ann Bjornsti
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DATABASES

Cancer.gov

breast cancer

endometrial cancer

LocusLink

4E-BP1

ASK1

BRCA1

cyclin D1

eIF2α

eIF4E

FKBP12

KIP1

LKB1

p53

PDK1

PP2A

PP4

PP6

PTEN

RAC1

RAP1A

RAP1-GAP

RAB5

RHEB

S6K1

TERT

TOR

TSC1

TSC2

Glossary

WD REPEAT

A protein-binding and small-ligand-binding motif that is present in the amino-acid sequence of several proteins.

SCAFFOLD PROTEIN

A protein with the primary function of bringing together proteins that share a common signalling pathway to allow for interaction between those proteins. Also referred to as docking proteins.

STAT3

A member of the STAT family of signalling proteins. Following activation, STAT3 forms a heterodimer with other STAT family members. This complex migrates to the nucleus to act as a transcription factor, activating genes that are involved in cell division and differentiation.

14-3-3 PROTEINS

This family of proteins bind to a phosphorylated serine residue within the 14-3-3 domain of target proteins. 14-3-3 proteins can induce several effects — altered interactions with other binding partners, changes in the localization within the cell, altered catalytic activity and altered stability of the target protein. 14-3-3 proteins have been implicated in several biological functions, including cell-cycle progression, signal transduction and apoptosis.

SMALL G PROTEINS

This family of small proteins mediate signalling by binding and hydrolysing GTP. The GTP-bound form is active. It interacts with and activates several effector proteins that mediate downstream signalling events. G proteins are regulated by proteins that accelerate GTP hydrolysis to GDP (GAPs), increase the rate of GTP binding (GEFs) or inhibit the release of GDP (GDIs).

ORNITHINE DECARBOXYLASE

Rate-limiting enzyme in the conversion of ornithine to putrescine. Putrescine and other polyamines are required for the division of normal cells.

LOSS OF HETEROZYGOSITY

(LOH). In cells that carry a mutated allele of a tumour-suppressor gene, the gene becomes fully inactivated when the cell loses a large part of the chromosome carrying the wild-type allele. Regions with high frequency of LOH are believed to harbour tumour-suppressor genes.

BCR–ABL

A fusion protein resulting from the translocation between a gene in the breakpoint cluster region (BCR) and the gene coding for the ABL tyrosine kinase. This fusion protein is responsible for some types of leukaemia.

HYPOCALCAEMIA

Low levels of calcium within the body.

THROMBOCYTOPAENIA

Low levels platelets in the blood.

MUCOSITIS

Inflammation of mucosa often seen as sores in the mouth.

LEUCOPAENIA

Low white-blood-cell count.

HYPERLIPIDAEMIA

Excess levels of lipids in the blood.

PHARMACODYNAMIC

The effects on the biochemistry of the body resulting from treatment with a drug or combination of drugs.

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Bjornsti, MA., Houghton, P. The tor pathway: a target for cancer therapy. Nat Rev Cancer 4, 335–348 (2004). https://doi.org/10.1038/nrc1362

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