Epidermal Growth Factor Receptor Expression and Resistance Patterns to Targeted Therapy in Non-Small Cell Lung Cancer: A Review

Abstract

Globally, lung cancer is the leading cause of cancer-related death. The majority of non-small cell lung cancer (NSCLC) tumours express epidermal growth factor receptor (EGFR), which allows for precise and targeted therapy in these patients. The dysregulation of EGFR in solid epithelial cancers has two distinct mechanisms: either a kinase-activating mutation in EGFR (EGFR-mutant) and/or an overexpression of wild-type EGFR (wt-EGFR). The underlying mechanism of EGFR dysregulation influences the efficacy of anti-EGFR therapy as well as the nature of resistance patterns and secondary mutations. This review will critically analyse the mechanisms of EGFR expression in NSCLC, its relevance to currently approved targeted treatment options, and the complex nature of secondary mutations and intrinsic and acquired resistance patterns in NSCLC.

Keywords: drug resistance; epidermal growth factor receptor; monoclonal antibody; non-small cell lung cancer; tyrosine kinase inhibitor.

Figure 1

A schematic representation of EGFR illustrating exon boundaries and associated extracellular, transmembrane, and intracellular protein domains. The extracellular domain is involved in ligand binding (Domains I and III) and dimerisation (Domain II). The intracellular domain contains a juxtamembrane domain, tyrosine kinase domain, and multiple C-terminal tyrosine residues (circles), which are phosphorylated on ligand binding and receptor activation leading to the activation of cell proliferation, survival, migration, and/or angiogenesis signalling pathways. The tyrosine kinase domain is expanded to show relevant mutations associated with resistance and sensitivity to first-, second- and third-generation tyrosine kinase inhibitors as discussed in Table 3. (large EGF binding domain 1, L1; cysteine-rich domain 1, CR1; large EGF binding domain 2, L2; and cysteine-rich domain 1, CR2).