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Targeting RAS signalling pathways in cancer therapy
Nature Reviews Cancervolume 3, pages11–22 (2003)Cite this article
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Key Points
RAS proteins, their regulators and the downstream enzymes that they control are activated in many tumour types by a variety of mechanisms, including oncogenic mutation ofRAS genes.
They are crucial mediators of several of the malignant characteristics of transformed cells and are therefore good candidates for tumour therapy.
RAS proteins require post-translational modification by farnesylation to be biologically active. Farnesyl transferase inhibitors have some antitumour activity in the clinic, but they seem to act through targets other than RAS.
Kinase inhibitors that block either RAF or mitogen-activated protein (MAP) kinase kinase MEK in the RAF/MAP kinase pathway downstream of RAS have been developed and show promise in early clinical trials.
Inhibitors acting on epidermal growth factor (EGF) receptor and ERBB2 upstream activators of RAS have been developed. Antibodies directed against ERBB2 have been licensed for the treatment of breast cancer, whereas small-molecule EGF receptor inhibitors show potential against lung cancer in clinical trials.
Other RAS-related therapies are in development, including inhibitors of AKT/PKB kinase activity, which is activated byRAS oncogenic mutation and byPTEN tumour-suppressor gene loss.
Abstract
The RAS proteins control signalling pathways that are key regulators of several aspects of normal cell growth and malignant transformation. They are aberrant in most human tumours due to activating mutations in theRAS genes themselves or to alterations in upstream or downstream signalling components. Rational therapies that target the RAS pathways might inhibit tumour growth, survival and spread. Several of these new therapeutic agents are showing promise in the clinic and many more are being developed.
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Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK
Julian Downward
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Glossary
- SH2 DOMAIN
Src homology 2 domain. A protein domain capable of binding tyrosine phosphorylated sites.
- SH3 DOMAIN
Src homology 3 domain. A protein domain capable of binding proline-rich motifs.
- AKT/PKB
A family of three closely related serine/threonine protein kinases containing amino-terminal pleckstrin homology domains that bind to the lipid products of phosphatidylinositol 3-kinase (PI3K). They are activated on PI3K stimulation and provide anti-apoptotic signals to the cell.
- FORKHEAD
A large superfamily of transcription factors, of which one family, FoxO, is phosphorylated and inhibited by AKT/PKB.
- BIM
A member of the BCL-2 family of apoptosis regulatory proteins. BIM induces apoptosis by acting at mitochondria to promote the release of cytochromec into the cytosol.
- FAS LIGAND
An extracellular protein that binds and activates the death receptor FAS, also known as CD95 and APO1, leading to initiation of apoptosis.
- p110α
One isoform of the catalytic subunit of phosphoinositide 3-kinase (PI3K). Type I PI3Ks are made up of either α, β, γ or δ forms of p110, together with a regulatory p85 subunit (for p110α, β and δ) or p101 subunit (for p110γ).
- IC50
The concentration of a drug giving a 50% inhibition of the activity of a target enzyme.
- RNA APTAMER
A synthetic RNA molecule selected for ability to interact with a target protein.
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Downward, J. Targeting RAS signalling pathways in cancer therapy.Nat Rev Cancer3, 11–22 (2003). https://doi.org/10.1038/nrc969
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