Like other ERBB receptor tyrosine kinases, epidermal growth factor (EGF) receptor (EGFR) regulates cell proliferation, motility and differentiation, and its deregulation is implicated in a range of epithelial cancers. Ferguson and colleagues have used X-ray crystallography to determine how the EGFR inhibitor cetuximab — which is now used to treat advanced-stage colorectal cancer — physically blocks EGFR signalling.

EGFR signalling is triggered by the dimerization of EGFR receptors. Dimerization requires the binding of EGF ligands — which include EGF itself, transforming growth factor-α, amphiregulin and betacellulin — to the EGFR extracellular region. These ligands bind two separate extracellular domains of EGFR — domains I and III — and alter the conformation of the receptor so that the dimerization domain (domain II) is exposed. This effectively traps the receptor in a conformation that can dimerize with its neighbour.

Cetuximab is a human:mouse chimeric monoclonal antibody that binds with high specificity to the extracellular domain of EGFR and prevents receptor dimerization and signalling. Ferguson and colleagues determined the crystal structure of the cetuximab antigen-binding (Fab) fragment in complex with the soluble extracellular region of EGFR. They found that the Fab fragment binds exclusively to domain III of the receptor and covers an epitope that partially overlaps with the growth-factor-binding site, and this blocks the access of the ligand to this key region.

Cetuximab not only prevents ligand binding, but the heavy-chain (VH) region of the antibody sterically prevents domain I of EGFR from adopting the conformation required for dimerization. Because the dimerization-competant conformation normally requires ligand binding, the importance of this conformational restriction is not yet clear. However, the authors point out that it could help to prevent potential ligand-independent modes of EGFR activation, perhaps through heterodimerization or homodimerization of EGFR when it or other ERBB receptors are aberrantly overexpressed.

The search for antagonistic ligand analogues to block EGFR signalling has not yet been successful, but the results of the present study raise the possibility that these analogues could be improved by fusing them to a more bulky molecule to enhance their potency. The authors also point out that the identification of the cetuximab epitope will be useful during screens for somatic mutations of EGFR that lead to increased or reduced sensitivity to the drug.