The biology of Epidermal Growth Factor Receptor (EGFR) from regulating cell cycle to promoting carcinogenesis: the state of art including treatment options

Abstract

Structure and function of egfr Receptor Tyrosine Kinases (RTKs) are cell surface receptors for many ligands such as polypeptide growth factors, cytokines, and hormones for which they have a high affi nity [1]. So far 58 RTKs have been identifi ed which are distributed in 20 families and amongst those, the Epidermal Growth Factor Receptor (EGFR) and its other family members (erbB2/ HER2, erbB3/ HER3, erbB4/HER4) have been discovered to play an important role in signalling and cancerogenesis [1]. These receptors can initiate intracellular signalling regulating cell proliferation and survival [2]. The mechanisms through which this happens and can be targeted by specifi c drugs is related to the structure and biology of the receptor itself [3]. The EGFR gene is located on the short arm of chromosome 7 (7p11.2) and encodes a 170-kDa type I transmembrane growth factor receptor with tyrosine kinase activity. All these trans-membrane proteins are composed of an extracellular ligand-binding domain, a transmembrane lipophilic domain, and an intracellular tyrosine kinase domain and all bind to receptor-specifi c ligands except HER2 [4]. After biding with its specifi c ligand, the receptor undergoes dimerization (homo or heterodimerisation according to the type of the other receptor involved in the process). The subsequent phosphorylation of the key tyrosine residues within the COOH-Abstract The current defi nition of cancer is the creation of atypical cells capable to rapidly grow beyond the normal boundaries and spread to distant organs. To do so tumour cells have to acquire to the ability to proliferate continuously and avoid apoptosis. An important role in this process is played by growth factors and their receptors. Amongst many, one of the most important interaction is between the Epidermal growth factor (EGF) and its receptor (EGFR) which are frequently mutated or upregulated in human cancers particularly in non-small cell carcinoma of the lung (NSCLC). The biding leads to protein activation, cell proliferation and decreased apoptosis. However, in this subset of tumours, the blockage of this interaction by EGFR-targeting drugs has shown an overall outcome improvement leading to the era of target therapy. The result is that patients are now routinely screened for a series of actionable mutations to be given the best possible therapy available for their specifi c type of tumour limiting the side effect of broad-spectrum chemotherapy. This paper will review the biology of EGFR receptor, the type and role of its mutation and the clinical implication for patients with NSCLC harbouring these mutations.