EGF receptor family

The ErbB receptor family, also known as the EGF receptor family or type I receptor family, is one of the best-studied receptor-protein tyrosine kinase groups, as it plays a general role in signal transduction and oncogenesis. This family consists of four members belonging to the ErbB protein line (ErbB1-4). The ErbB proteins function as homo- and heterodimers. These receptors contain an extracellular domain consisting of four parts: domains I and III are leucine-rich segments involved in growth factor binding (except for ErbB2), and domains II and IV contain several disulfide bonds. In addition, domain II is involved in the formation of both homo- and heterodimers within the ErbB/HER protein family.

Seven ligands bind to EGFR, including epidermal growth factor and transforming growth factor-alpha, none bind to ErbB2, two bind to ErbB3 and seven ligands bind to ErbB4. The extracellular domain is followed by a single transmembrane segment of about 25 amino acid residues and an intracellular portion of about 550 amino acid residues containing (i) a short juxtamembrane segment, (ii) a protein kinase domain and (iii) a carboxy-terminal tail. ErbB2 has no known activating ligand.

ErbB receptors are activated after homodimerization or heterodimerization. The ErbB family is unique among the various groups of receptor tyrosine kinases (RTKs) in that ErbB3 has restricted kinase activity, whereas ErbB2 has no direct ligand. Therefore, heterodimerization is an important mechanism that allows activation of all ErbB receptors in response to ligand stimulation.

The ErbB2-ErbB3 heterodimer complex is the most active dimer of the family. These receptors are involved in the development of a large proportion of lung and breast cancers, which are the first and second most common cancers worldwide (excluding skin cancer). Around 20 % of non-small cell lung cancers have activating mutations in EGFR. More than 90 % of these patients have exon 19 deletions (746ELREA750) or the exon 21 substitution L858R.

The activated ErbB receptors bind to many signaling proteins and stimulate the activation of many signaling pathways. The specificity and efficacy of intracellular signaling pathways is determined by positive and negative regulators, the specific composition of the activating ligand(s), the components of the receptor dimer, and the diverse proteins associated with the tyrosine-phosphorylated C-terminal domain of ErbB receptors (Wang Z 2017).

ErbB receptors are overexpressed or mutated in many types of cancer, particularly in breast cancer, ovarian cancer and non-small cell lung cancer. The overexpression and overactivation of ErbB receptors is associated with poor prognosis, drug resistance, cancer metastasis and lower survival rates. The ErbB receptors, particularly EGFR and ErbB2, are the most important targets for the development of cancer therapies (Hynes NE et al. 2009).

Gefitinib and erlotinib are orally active reversible type I EGFR mutation inhibitors that bind to an active enzyme conformation. Osimertinib is an irreversible type VI inhibitor that forms a covalent bond with C797 of EGFR and is FDA-approved for the treatment of patients with this mutation; type VI inhibitors generally form a covalent adduct with their target protein.

Approximately 20% of breast cancer patients have amplification of the ErbB2/HER2 gene on chromosome 17q. One of the first targeted treatments for cancer was the development of trastuzumab, a monoclonal antibody that interacts with the extracellular domain of ErbB2/HER2, thereby downregulating it. Surgery, radiotherapy, chemotherapy with cytotoxic drugs and hormonal modulation are the mainstays in the treatment of breast cancer. In addition, lapatinib and neratinib are FDA-approved small molecule ErbB2/HER2 antagonists used to treat select breast cancer patients. Of the approximately 30 FDA-approved small molecule protein kinase inhibitors, five are irreversible type VI inhibitors, four of which, including afatinib, osimertinib, dacomitinib and neratinib, target ErbB family receptors (ibrutinib is the fifth and targets Bruton's tyrosine kinase). Avitinib, olmutinib and pelitinib are other type VI inhibitors currently in clinical trials for non-small cell lung cancer that target EGFR. Secondary resistance to both targeted and cytotoxic drugs is the rule, and the development and implementation of strategies to minimize or overcome resistance is an important goal in cancer therapy.

1. Hynes NE et al (2009) ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol 21:177-84.
2. Roskoski R Jr (2019) Small molecule inhibitors targeting the EGFR/ErbB family of protein-tyrosine kinases in human cancers. Pharmacol Res 139:395-411.
3. Wang Z (2017) ErbB Receptors and Cancer. Methods Mol Biol 1652:3-35.