Targeting the Epidermal Growth Factor Receptor in Colorectal Cancer

European Oncological Disease, 2007;1(1):108-112


A crucial goal in the refinement of systemic cancer therapy is the achievement of high efficacy while minimising side effects. Conventional anticancer drugs target malignant cells to an extent, but are often associated with dose-limiting toxicity. One solution is to improve the specificity of the therapeutic agent based upon knowledge of a specific target. As our understanding of the molecular basis of cancer steadily progresses, the opportunities for the development of such improved treatments rise commensurately. The design of modern drug therapies is informed by the genetic and biochemical mechanisms responsible for the behaviour of malignant cells. One such endeavour includes the development of targeted drugs against the type I transmembrane kinase receptor epidermal growth factor receptor (EGFR). Following a brief outline of EGFR cancer biology, this article will provide an up-to-date synopsis of clinical research efforts attempting to exploit this receptor system in the setting of advanced colorectal cancer.

Citation European Oncological Disease, 2007;1(1):108-112

The Epidermal Growth Factor Receptor Family
EGFR was the earliest of four receptors discovered in the ErbB family of receptor tyrosine kinases.1,2 Furthermore, it was this receptor that first identified a relationship between an activated oncogene and malignant transformation.3 This 170kDa glycoprotein comprises an extracellular portion made up of four distinct sub-domains capable of conformational change.4,5 It is anchored by a single-pass transmembrane domain that connects to a cytoplasmic tail harbouring tyrosine kinase activity.6 EGFR and its three sibling receptors – HER-2/ErbB2, HER-3/ErbB3 and HER-4/ ErbB4 – transduce the effects of at least 11 different peptide ligands, including epidermal growth factor (EGF).7 Signalling events initiated by such growth factors are involved in normal physiological cellular growth and proliferation, but are critically important in malignant transformation.

The harbinger of growth factor signalling is the extracellular binding of ligands to one or more of these receptors, which induces receptor homoor hetero-dimerisation or oligomerisation. As a result, phosphorylation of kinase-domain tyrosine residues ensues. These serve as docking sites for various cytoplasmic proteins, which then propagate signalling via second messenger pathways through the cytoplasm. These include Ras/mitogenactivated protein (MAP) kinase, the Src kinase family, Janus kinase (JAK), signal transducer and activator of transcription (STAT), phosphoinositol 3 (PI3), kinase/Akt and other phospholipid metabolism pathways. Via induction of nuclear transcription factors, the end-product of signalling is stimulation of cellular processes such as proliferation, antiapoptosis, growth and migration.6 Ligand stimulation also leads to increased internalisation of EGFR via endocytic pathways; ultimately, receptors are either recycled or destined for lysosomal degradation.8 The system is hugely complex in that there are multiple levels of variability and control, which increases system robustness.9,10 On one level, there are interactions between different receptors and their ligands; on another, receptor– receptor interactions can form oligomer lattices, which in turn force interactions within the second-messenger and output layers.

Overactivation of this signalling mechanism can be due to increased ligand stimulation,11 receptor overexpression12 or by mutations leading to constitutive activity or enhanced function,13 and has been frequently observed in a wide range of epithelial tumour types. Furthermore, such parameters are associated with poorer clinical outcome.14 Taken together, these factors make EGFR and its receptor family extremely attractive therapeutic targets.

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