Update on HER-2 as a target for cancer therapy: alternative strategies for targeting the epidermal growth factor system in cancer

Abstract

The epidermal growth factor (EGF) family of ligands and receptors interact to influence cell division, differentiation and motility. Much evidence supports their importance in causing and sustaining cell transformation in model systems and in human cancer. The exact mechanism by which this is achieved varies in different tumour types and from case to case. The EGF system is a target for new types of targeted chemotherapy. The choice of strategy will depend on the mechanism involved, however, and several approaches are under development or evaluation in clinical trials. Each will have a different spectrum of side effects and the potential for development of drug resistance.

Figure 1

The epidermal growth factor family of ligands and receptors transform cells by different mechanisms. (A) A cell may express a normal level of receptors, but these are over-active because of the presence of excess levels of one or more ligands. The mechanisms by which excessive amounts of ligands are produced are not well established, but are not due to gene amplification. Some evidence suggests that other systems, such as G-protein-coupled receptors (GPCRs), may influence ligand processing by metalloproteases. (B) A cell may over-express a receptor as a result of either gene amplification or increases in transcription, or both. (C) Some cancers, notably brain tumours, express mutant receptors that are partly constitutively active. The expression, processing and bioavailability of ligands can be targeted to suppress their actions. Receptors can be targeted by antibodies, which may inhibit ligand binding or have other activities, or by antibodies fused with toxic molecules or with small molecule tyrosine kinase inhibitors.