The HER family and cancer: emerging molecular mechanisms and therapeutic targets

Abstract

The human epidermal growth factor receptor (HER) family of transmembrane tyrosine kinases regulates diverse cellular functions in response to extracellular ligands. The deregulation of HER signaling through gene amplification or mutation is seen in many human tumors and an abundance of experimental evidence supports the etiological role of these events in cancer pathogenesis. In addition, the fact that they are feasible targets for both antibody and small-molecule therapeutics has made them highly pursued targets for the development of rationally designed anticancer drugs. Several HER-targeting agents have entered clinical practice and this has led to novel discoveries regarding the mechanisms of resistance, which has defined a new generation of challenges for targeted cancer therapies. Here, we review recent advances in our understanding of HER signaling and targeting in cancer.

Figure 1. The structural basis for the activation of HER proteins

The extracellular regions of HER proteins are composed of four domains numered I,II,III, and IV. Domains I and III are ligand binding domains, and domains II and IV are cysteine-rich domains which bind each other and other receptors. The tyrosine kinase domain has two lobes which are shared among the tyrosine kinase family and are termed the n-terminal and c-terminal lobes. The c-terminal tail contains many tyrosines which are targets for phosphorylation. When unliganded, the ECD is folded into a closed conformation due to an intramolecular interaction between domains II and IV (see inactive monomer). The HER ligand bind domains I and III bringing them together. The result is a refolding that exposes domain II which is the dimerization interface (see active monomer). The dimerization domains of two active receptors interact, bring the intracellular domains in close proximity and the interaction of the two kinase domains results in transphosphorylation (see dimer).