Introduction to Epithelial Growth Factor Receptor

  • There are some antibodies:

    1. Nimotuzumab

    Anti-EGFR antibody (Nimotuzumab) is a humanized antibody of IgG that binds to an EGFR.      

    1. Necitumumab

    Necitumumab (proposed INN) is a monoclonal antibody and an antineoplastic, which binds to the epidermal growth factor receptor (EGFR).      

    What is EGFR?

     

    Epithelial growth factor receptor (EGFR) has tyrosine kinase activity. Once combined with epidermal growth factor (EGF), EGFR can activate related genes in the nucleus, thus promoting cell division and proliferation. The expression of EGFR is increased in gastric cancer, breast cancer, bladder cancer and head and neck squamous cell carcinoma.

    EGFR is a large transmembrane glycoprotein with a molecular weight of about 180 kD. It has ligand-induced tyrosine protein kinase activity. It is a member of ErbB, a conservative receptor family. Other members of this family include HER2/Neu/ErbB2, HER3/ErbB3 and HER4/ErbB4. ErbB receptors are commonly characterized by an extracellular (EC) ligand binding region, a single transmembrane region consisting of two repetitive cysteine-rich regions, and intracellular sequences containing tyrosine protein kinases and self-phosphorylation sites.

    Structure of EGFR

    EGFR is a receptor tyrosine kinase (RTK), located on chromosome 7 and composed of 28 exons and encodes 1186 amino acids. The relative molecular weight of the glycoprotein is about 170,000. It consists of three parts: an extracellular functional domain that binds to EGF, a short transmembrane (TM) and an intracellular domain that has tyrosine kinase activity. Extracellular domain (ECD): At the N-terminal, there are 621 amino acid residues, consisting of four sub-regions; TM: a hydrophobic region consisting of 23 amino acid residues and a single-chain alpha helix; Intracellular region: 542 amino acid residues, consisting of three sub-regions: JM, tyrosine kinase (TK) and C-terminal.

    Activation of EGFR

    Activation of EGFR generally requires ligand activation. In the EGFR family, almost all of them have their corresponding ligands, except ErbB2. When EGFR binds to ligands, there are three main activation processes: (1) after ligand binds to EGFR, the three-dimensional conformation of EGFR is changed to form a homologous dimer or EGFR binds to another member of ErbB family to form a heterodimer; (2) tyrosine kinase region of EGFR is activated, which binds to an ATP molecule and phosphorylates the tyrosine residue of the receptor in the dimer; Substrate enzymes of SH2 protein are identified in turn, and signal is transmitted to human cells to stimulate cell growth and proliferation.

    The correlation between EGFR and some tumors

    EGFR is stably expressed in various epithelial tissues, interstitial and neuronal tissues. Studies have shown that overexpression and/or mutation of EGFR can lead to multiple tumors. The association between EGFR and non-small cell lung cancer (NSCLC) has been the most studied, but in recent years, EGFR mutations have been detected in other tumors. Up to now, the overexpression of EGFR has been found in many solid tumors. After the analysis of EGFR gene in cancer patients, it was found that most patients had deletion of exon 19 of EGFR or missense mutation of exon 21 of EGFR in chromosome L858R. This mutation will lead to downstream signal changes, abnormal induction of MAPK ERK1/2 signal, accompanied by cell proliferation and changes in sensitivity to EGFR phosphatase inhibitors. These changes make EGFR overexpression, cell signal transduction enhanced, cell proliferation, differentiation, migration increased, and eventually lead to malignant transformation.

    EGFR and targeted therapy of tumors

    Growth factor signaling pathways play an important role in many physiological and pathological processes, such as growth, proliferation, development and apoptosis. Disruption of growth factor signaling pathways through multiple pathways may lead to tumorigenesis. EGFR signal plays an important role in controlling the occurrence of multiple epithelial tumors. Therefore, malignant transformation and poor prognosis of tumors can be controlled by regulating EGFR signal.

    EGFR antagonists

    With the further study of the relationship between signal transduction and cancer, researchers put forward the concept of signal transduction intervention therapy, that is, to intervene in the abnormal link of signal transduction pathway in order to achieve the purpose of inhibiting the growth of cancer. Overexpression and/or mutation of EGFR in many tumors are closely related to the occurrence, development and prognosis of tumors. EGFR can be used as a target to study the antagonists in its signal transduction pathway and find drugs to treat tumors. At present, the main antagonists used are EGFR monoclonal antibodies and small molecule tyrosine kinase antagonists. Compared with other chemotherapeutic drugs, monoclonal antibodies have the characteristics of high efficacy and low side effects. Small molecule tyrosine kinase inhibitors can competitively inhibit the binding of ATP to intracellular tyrosine kinase domain of EGFR, thereby affecting the phosphorylation of tyrosine residues and inhibiting downstream signal transduction of EGFR.

    Targeted therapeutic effect of natural substances

    Receptor molecule can induce invagination through the strong mediation of sorting signal, and the affinity with agonist is greatly reduced after the invagination of receptor. If a substance is found to promote the invagination of EGFR or increase the invagination time of EGFR, the substance can prove to inhibit the activity of EGFR and play an anti-tumor role.

    Targeted therapy of nanoparticle delivery system

    In addition to the direct effects of modification, modification or inhibition of EGFR, researchers have also adopted an indirect and simpler method to treat tumors induced by EGFR changes. The researchers transfected the B-type nanoparticle delivery system modified with EGFR into Panc-1 cells in vitro. The EGFR in the delivery system can specifically bind to EGF, thus reducing the concentration of free EGF and achieving the effect of targeted therapy for pancreatic cancer. Compared with the previous non-modified nanoparticle delivery system, this method is featured by high transfection rate, good integration effect and high safety for the treatment of pancreatic cancer and even other types of cancer.

    EGFR plays an important role in the occurrence and development of tumors. As an important target, EGFR provides a new way for the diagnosis and treatment of tumors. In the development of tumors, tumors caused by disorders of EGFR signal transduction account for a considerable proportion. The abnormal expression of EGFR can regulate the proliferation, angiogenesis, adhesion, invasion, metastasis and apoptosis of tumor cells. Antineoplastic drugs targeting EGFR have also been applied to tumors. By exploring the function of EGFR signaling pathway and its relationship with tumorigenesis and development, we can further understand the mechanism of EGFR. However, there is little research on the important node genes in EGFR signaling pathway in tumorigenesis and development. Therefore, node genes in EGFR signaling pathway will be the future focus of tumors development research.