21.1

Introduction

EGFR stands for epidermal growth factor receptor. It was discovered in 1968 as the

first member of the ErbB/HER family (Bhatia et al. 2020). Cohen was awarded the

Nobel Prize in Medicine for the discovery of growth factor known as epidermal

growth factor (EGF) and its receptor in 1986 (Mendelsohn 2001). EGFR is a

cytomembrane ligand-gated protein channel that is prompted when specific ligands

bind to the catalytic domain of the protein. The specific ligands include EGF and

TGFα (Sternlicht and Sunnarborg 2008). Binding of specific ligands results in the

transition of inactive monomeric form to the active homodimeric form. Upon

dimerization, the congenital intracellular tyrosine kinase activity of EGFR is

stimulated. This acceleration of kinase activity upshot in autophosphorylation of

several tyrosine (Y) residues in the C-terminal domain. The tyrosine residues

autophosphorylated were Y992, Y1045, Y1068, Y1148 and Y1173. All these events

finally activate the downstream signalling responses of the cell through the SH2

domains of the phosphorylated domains.

Several signal communication streams or networks like MAPK, Akt and JNK

pathways are prompted, which urges to DNA synthesis and cell escalation. The

ability of the kinase domain of EGFR to cross-phosphorylate the tyrosine residue of

other receptors also results in self-activation of the protein and thus may cause

oncogenesis (Kumar et al. 2021; Kenney et al. 2003). As a growth factor receptor,

the EGFR was the first protein to be identified in malignant cells (Carpenter et al.

1975). The recognition of EGFR as an oncogene has led to the expansion of different

strategies to overcome over-activation and resistance issues. Different strategies

adapted include:

1. Conjugated immune toxin: The receptor ligands or antibodies are exposed to the

environment of immune toxins or recombinant molecules. Example is diphtheria

toxin-human epidermal growth factor fusion protein (DAB (389) EGF), in this

the toxin used is diphtheria toxin and the receptor ligand is EGF.

2. Monoclonal antibodies: Monoclonal antibodies bind to the ectodomain of EGFR

that leads to the repression of downhill signalling. Cetuximab, panitumumab,

necitumumab and nimotuzumab are the anti-EGFR monoclonal antibodies (Paez

et al. 2004).

3. Adaptor protein inhibition: Adaptor proteins are the molecules that are essential

to influence the downstream signalling and thus regulate cellular proliferation. To

inhibit cellular proliferation, the adaptor proteins need to be inhibited. Cbl

ubiquitin ligase, Grb-7/2 and APPL1 are the examples of EGFR-associated

adaptor proteins that lead to oncogenesis (Bhatia et al. 2020).

4. Kinase inhibition: Kinases are the protein molecules that are reported to be

overexpressed in different malignancies. To date, there are 52 FDA-approved

kinase inhibitors. Among these, the quinazoline-based anti-EGFR kinases are

gefitinib (Rawluk and Waller 2018), erlotinib, afatinib, brigatinib, icotinib and

osimertinib (Yarden and Schlessinger 1987).

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