Targeting RAS signalling pathways in cancer therapy

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Abstract
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.