EGFR belongs to the ErbB family of transmembrane tyrosine kinase receptors ( ErbB comprises ErbB1/EGFR/HER1, ErbB2/HER2/NEU, ErbB3/HER3, and ErbB4/HER4 ).
EGFR exists as a monomer and can initiate the signaling cascade in response to epidermal growth factor ligand by itself through homodimerization or heterodimerization ( by transactivation of other HER family receptors ) resulting in growth and apoptosis.
EGFR exists in an equilibrium that controls its ability to transition from an inactive to an active state and vice versa. In an active state, it allows for transfer of a phosphate from adenosine triphosphate, bound to its kinase domain, to peptide substrates downstream to sustain cell growth and proliferation. It has an extracellular domain and an intracellular domain, and serves as an enticing molecule for targeted therapies. The intracellular kinase domain serves as a binding site for tyrosine-kinase inhibitors ( TKIs ).
Mutations in exons 18–21 of EGFR form therapeutic targets in non-small-cell lung carcinoma ( NSCLC ).
The structural changes as a result of the mutation are located within the adenosine triphosphate binding domain of the kinase.
Mutations such as G719X mutation in exon 18, in frame deletions or insertion of exon 19, and L858R or L861Q mutation in exon 21 are considered as the classic or sensitizing EGFR mutations in NSCLC.
Approximately 90% of these sensitizing mutations are exon 19 deletion or exon 21 L858R point mutation. These mutations lead to increased kinase activity of EGFR, leading to the hyperactive downstream pathway and resulting in increased prosurvival signals.
The exon 19 deletion and exon 21 L858R point mutation lead to a decreased adenosine triphosphate binding affinity in favor of a much higher affinity for small-molecule TKIs when compared with wild-type EGFR.
The EGFR-sensitizing mutations are more prevalent in patients with adenocarcinoma histology of NSCLC, never smokers or light smokers, women, and people of East Asian descent.
The frequency of EGFR mutation can be as high as 50% in never smokers of Asian descent.
Exon 20 insertions ( except A763_Y764 insFQEA mutation ) and T790M mutation confer resistance to EGFR TKIs.
Gefitinib ( Iressa ) and Erlotinib ( Tarceva ), first-generation small-molecule EGFR TKIs, are reversible inhibitors of EGFR and were approved for clinical use prior to our understanding of the role of EGFR mutation status in NSCLC.
However, the role of somatic EGFR mutations as predictive biomarkers of response and resistance to EGFR TKIs has since then been validated and is now well established.
Clinical trials like OPTIMAL ( CTONG-0802, a randomized, open-label, phase III study of first-line Erlotinib versus chemotherapy in patients with advanced EGFR mutation-positive NSCLC ) and IPASS ( Iressa Pan Asia Study ) have shown clear improvements in response rates and progression-free survival ( PFS ) with Erlotinib and Gefitinib, respectively, in the first-line setting when compared with Platinum-based chemotherapy.
Despite an initial response with TKIs, the median time to disease progression is generally within 10-13 months of therapy due to development of resistance to EGFR-directed therapy.
The most common cause of acquired resistance to EGFR TKIs is the development of a missense mutation in exon 20 of the EGFR kinase domain, T790M.
Other mechanisms of resistance to EGFR TKIs include bypass of carcinogenesis via other genomic drivers ( hepatocyte growth factor receptor or MET, ErbB2 ), epithelial to mesenchymal transition, and transformation into high-grade small cell histology.
Approximately 49–63% of patients with resistance to first-line EGFR TKIs will have T790M missense mutation. This confers resistance by increasing the affinity of the binding site for ATP instead of small-molecule TKIs.
Clonal selection of cells harboring this mutation over time is thought to lead to refractoriness to Erlotinib and Gefitinib.
Therefore, increased interest in circumventing this problem led to the development of second-generation TKIs, eg, Afatinib ( Giotrif ), which irreversibly bind to the catalytic site using covalent bonds. ( Xagena )
Joshi M et al, Cancer Manag Res 2015; 7: 75–82