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_targeting RAS signalling pathways in cancer therapy

Nature Reviews Cancer volume 3, pages 11–22 (2003)Cite this article

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 of RAS 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 by RAS oncogenic mutation and by PTEN 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 the RAS 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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Figure 1: Signalling upstream of RAS.
Figure 2: Signalling downstream of RAS.

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Authors and Affiliations

  1. Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK

    Julian Downward

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DATABASES

Cancer.gov

breast carcinoma

colon carcinoma

colorectal cancer

head and neck cancer

leukaemia

melanoma

non-small-cell lung carcinoma

ovarian carcinoma

prostate carcinoma

renal-cell carcinoma

stomach carcinoma

LocusLink

ABL

AKT

BCR

CDC42

EGFR

ELK1

ERBB2

FOS

FoxO family

GRB2

HRAS

HSP90

ICMT

JUN

KRAS

MAPKs

MEK1

MEK2

NF1

NRAS

PDK1

PTEN

RAC

RAF

RALBP1

RALGDS

RGL

RB

RGL2

RHO

SHC

SOS1

SOS2

TP53

TGF-α

VEGF

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 cytochrome c 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 Cancer 3, 11–22 (2003). https://doi.org/10.1038/nrc969

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