The family of ERBB or epidermal growth factor (EGF) receptors includes four members: EGFR/ERBB1, ERBB2, ERBB3 and ERBB4. EGFR and ERBB2 are involved in development of numerous types of human cancer and they have been intensely pursued as therapeutic targets.
Two important types of ERBB inhibitor are in clinical use: humanized antibodies directed against the extracellular domain of EGFR or ERBB2, and small-molecule tyrosine-kinase inhibitors (TKIs) that compete with ATP in the tyrosine-kinase domain of the receptor.
In preclinical models, treatment of tumour cells with ERBB-directed TKIs and antibodies rapidly downregulates phosphatidylinositol-3-kinase–AKT, mitogen-activated protein kinase, SRC, and signal transducer and activator of transcription (STAT) signalling, and blocks the proliferation of tumour cells. In the clinic, skin biopsies (surrogate tissue), and to a limited extent tumours, have been analysed for the molecular consequences of treatment with ERBB inhibitors.
ERBB-directed therapeutics have demonstrated clinical efficacy; however, the antitumour effects are often not as strong as predicted from preclinical studies. There are likely to be various reasons why this is so, an important one being that other tumour-cell alterations influence the tumour response to ERBB-targeted inhibitors. Therefore, rational drug-combination strategies have great potential to combat the complexity of tumour biology.
ERBB receptor tyrosine kinases have important roles in human cancer. In particular, the expression or activation of epidermal growth factor receptor and ERBB2 are altered in many epithelial tumours, and clinical studies indicate that they have important roles in tumour aetiology and progression. Accordingly, these receptors have been intensely studied to understand their importance in cancer biology and as therapeutic targets, and many ERBB inhibitors are now used in the clinic. We will discuss the significance of these receptors as clinical targets, in particular the molecular mechanisms underlying response.
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We would like to thank A. Badache and T. Schlange for critically reviewing the manuscript. The laboratory of N.E.H. is supported by the Novartis Research Foundation and grants from the Swiss Cancer League and the European Union.
During the preparation of this review, Heidi A. Lane was employed by Novartis; Nancy E. Hynes was a Novartis consultant.
- G-PROTEIN-COUPLED RECEPTORS
A large family of receptors that span the membrane seven times and couple to G proteins, which are composed of α-, β- and γ-subunits. The α-subunit contains the nucleotide (GTP or GDP) binding site, and the β- and γ-subunits behave as a single entity.
Commonly refers to the growth of tumour cells as tumours in immunocomprised mice.
- SURROGATE TISSUE
To examine the in vivo efficacy of tyrosine-kinase inhibitors targeted at epidermal growth factor receptor (EGFR) in cancer patients, skin biopsies of treated patients have been examined for downregulation of EGFR phosphorylation.
A form of bioregulation in which a secreted peptide affects only the cell from which it is secreted.
A form of bioregulation in which a secreted peptide affects a neighbouring cell.
A therapy that is given before the main treatment, which could be, for example, surgery.
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Hynes, N., Lane, H. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5, 341–354 (2005). https://doi.org/10.1038/nrc1609
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