The Epidermal growth factor receptor family (EGFRs) identified in cancer cells as the first growth factor receptor belongs to the receptor tyrosine kinases. The EGFR family includes four members: EGFR, ERBB2, ERBB3 and ERBB4. Each EGFR family member mainly contains three parts, including an extracellular region, a single transmembrane region and an intracellular tyrosine kinase domain.
EGFRs can regulate numerous intracellular processes via the interaction with their ligands which are EGFs family members. EGFRs can undergo homo- or hetero-oligomerization with other family members, when the extracellular domain of EGFRs are activated which can proceed conformational change. The EGFR family proteins can form homodimers or heterodimers by binding to their extracellular ligands with other family members. EGFR, also named HER1, can bind the following ligands, such as EGF, amphiregulin, TGF-α, betacellulin and so on. EGFR can regulate cell proliferation, survival and differentiation and other signal pathways. The ligands of ERBB4 contains the neuregulins, betacellulin and heparin-binding EGF-like growth factor. However, the ligand of ERBB2 have not been identified. Because of lacking an active kinase domain, ERBB3 is activated by forming dimers with a different ERBB family member.
EGFR family members play an important role in the development of early embryogenesis, the formation of central nervous system and the growth of heart and skin. If the body has deficiency in any one of EGFR family members, it will cause problems with the animal physiology. EGFR family members can involve in multiple diseases. For example, EGFR can cause psoriasis, cancer and inflammation. ERBB2 can leads to cancer and heart disease. ERBB4 can results in Alzheimer's disease. Therefore, researchers consider the EGFR family as a significant target to undergo clinical testing and cancer treatment in recent years.
EGF (epidermal growth factor) is the founding member of the EGF family of proteins, which also include Amphiregulin (AREG), Betacellulin (BTC), Epiregulin (EPR), HB-EGF, Neuregulins, and others. Members of epidermal growth factor family have highly similar structural and functional characteristics. They have at least one common structural motif, the EGF domain, which consists of six conserved cysteine residues forming three disulfide bonds. The main structure of EGF domain is a two-stranded beta-sheet followed by a loop to a C-terminal short two-stranded sheet. In addition to their EGF domain, the epidermal growth factor family members are characterized by two features: Production of mitogenic responses in EGF-sensitive cells, and high affinity binding to the EGF receptor.
The activity of epidermal growth factor family members is mediated by the epidermal growth factor receptor tyrosine kinases (EGFR/ErbB). Members of the EGFR/ErbB family are made up of an extracellular region or ectodomain that contains approximately 620 amino acids, a single transmembrane spanning region and a cytoplasmic tyrosine kinase domain. The extracellular domain of the EGF receptor is characterized by its capacity to bind EGF and EGF-like ligands with high affinity. The hallmark of the cytoplasmic portion of epidermal growth factor receptor is the sequence defining the tyrosine kinase domain. Near the carboxyl terminus of the receptor are four sites of EGF-dependent autophosphorylation.
Epidermal growth factor plays an important role in the regulation of cell growth, proliferation, and differentiation. EGF acts by binding to EGF receptor (EGFR) on the cell surface and stimulating the intrinsic protein-tyrosine kinase activity of the receptor, and initiates a signal transduction cascade. As a result a variety of biochemical changes take place within the cell, including increased intracellular calcium levels, glycolysis and protein synthesis and transcription of certain genes, which ultimately lead to DNA synthesis and cell proliferation. Members of epidermal growth factor family are known to be involved in tumor formation. The mediations of EGF therapy are so far mainly based on inhibiting the EGF receptor.
Human carcinomas frequently express high levels of receptors in the EGF receptor family, and overexpression of at least two of these receptors, the EGF receptor (EGFr) and closely related ErbB2, has been associated with a more aggressive clinical behavior. Further, transfection or activation of high levels of these two receptors in nonmalignant cell lines can lead to a transformed phenotype. For these reasons, EGFR inhibitiors directed at preventing the function of these receptors have the potential to be useful for EGF treatment in cancer. In the last two decades monoclonal antibodies (MAbs) which inhibit activation of the EGFR and ErbB2 have been developed. These MAbs have shown promising preclinical activity and 'chimeric' and 'humanized' MAbs have been produced in order to obviate the problem of host immune reactions. Clinical activity with these antibodies has been documented: trastuzumab, a humanized anti-ErbB2 MAb, is active and was recently approved in combination with paclitaxel for the treatment of patients with metastatic ErbB2-overexpressing breast cancer; IMC-C225, a chimeric anti-EGFr MAb, has shown impressive activity when combined with radiation treatment and reverses resistance to chemotherapy.
In addition to antibodies, compounds that directly inhibit receptor tyrosine kinases have shown preclinical activity and early clinical activity has been reported. A series of phase III studies with these antibodies and direct tyrosine kinase inhibitors are ongoing or planned, and will further address the role of these active anti-receptor agents in the treatment of patients with cancer.