The erbB Family: Targets for Therapeutic Development Against Cancer and Therapeutic Strategies Using Monoclonal Antibodies and Tyrosine Kinase Inhibitors

Abstract

The overexpression and aberrant function of members of the erbB family of receptors, particularly erbB1 (also known as epidermal growth factor receptor), and its ligands in many human cancers have provided a rationale for targeting this signaling network with novel approaches. erbB1 is a selective target for inhibiting cancers because its activation often confers a proliferative advantage. Activation of the erbB1 tyrosine kinase provides signals that drive dysregulated proliferation, invasion, metastasis, angiogenesis, and cell survival, and its inhibition has potential in both the treatment and prevention of these malignancies. Based on the structure and function of erbB1, two therapeutic strategies have been developed. The first uses human monoclonal antibodies (MAbs) generated against the receptor's ligand-binding extracellular domain. These MAbs block binding of receptor-activating ligands, and, in some cases, can induce receptor endocytosis and downregulation. The second uses small molecules that compete with adenosine triphosphate (ATP) for binding to the receptor's kinase pocket, thereby blocking receptor activation and the transduction of postreceptor signals. Early clinical studies suggest that both approaches are well tolerated and can induce clinical activity in many common malignancies.