What is EGFR (Epidermal Growth Factor Receptor)?
EGFR is a transmembrane glycoprotein receptor tyrosine kinase normally found on the surface of epithelial cells that regulates cell growth, proliferation, differentiation, and survival through activation of downstream signaling pathways. 1
Structural and Functional Characteristics
EGFR is a cell surface receptor belonging to the ErbB family of tyrosine kinase receptors, which includes four members: EGFR/HER1/ErbB1, HER2/ErbB2, HER3/ErbB3, and HER4/ErbB4. 1, 2
Normal Physiological Function
EGFR is expressed on both normal and cancer cells and plays essential roles in germline development and maintenance of adult tissues including the placenta, gut, liver, bone, skin, brain, pancreas, kidneys, mammary glands, and lungs. 3, 4
When EGFR binds to its cognate ligands (including epidermal growth factor [EGF] and transforming growth factor-alpha [TGF-α]), it triggers receptor dimerization, autophosphorylation of tyrosine residues, and activation of multiple intracellular signaling cascades. 1, 5
The activated signaling pathways include MAPK, PI3K/Akt/mTOR, and other cascades that regulate cellular proliferation, differentiation, migration, apoptosis, and survival. 1, 5
Tissue Distribution
EGFR is constitutively expressed by normal epidermal and follicular keratinocytes in the basal layer of the epidermis, in the outer root sheath of hair follicles, in sebaceous and eccrine epithelium, by dendritic cells, and various connective tissue cells. 1
EGFR stimulation accelerates wound healing, stimulates vasoconstriction and keratinocyte migration, and is essential for regulation of keratinocyte biology including cell cycle progression and differentiation. 1
Clinical Significance in Cancer
Overexpression and Mutations
EGFR is overexpressed in greater than 90% of head and neck squamous cell carcinomas and is frequently overexpressed in a variety of human malignancies including lung cancer, colorectal cancer, hepatocellular carcinoma, and glioblastoma. 1
Overexpression and/or dysregulation of EGFR is associated with poor prognosis, decreased survival, and resistance to chemotherapy and radiation in multiple tumor types. 5, 2
EGFR Mutations in NSCLC
The most commonly described activating mutations in EGFR (exon 19 deletions and p.L858R point mutation in exon 21) are associated with responsiveness to EGFR tyrosine kinase inhibitor therapy. 1
Less common alterations including exon 19 insertions, p.L861Q, p.G719X, and p.S768I (cumulatively accounting for ~10% of EGFR-mutated NSCLC) are also associated with TKI responsiveness, though studied in fewer patients. 1
Some EGFR mutations predict resistance to TKI therapy, including most EGFR exon 20 insertions and p.T790M (when present before TKI exposure, though p.T790M commonly emerges as an acquired resistance mechanism after initial TKI therapy). 1
EGFR mutations are more frequent in never/light smokers, women, patients with adenocarcinoma histology, and patients with East Asian ethnicity, though these clinicopathologic features should not be used to select patients for testing. 1
Therapeutic Targeting
Classes of EGFR Inhibitors
Two main pharmacologic approaches exist for inhibiting EGFR: monoclonal antibodies that block ligand binding to the extracellular domain, and small-molecule tyrosine kinase inhibitors that prevent intracellular tyrosine kinase phosphorylation. 5, 2
Monoclonal Antibodies
Cetuximab (a chimeric IgG1 antibody) and panitumumab (a fully human IgG2 antibody) are approved for treatment of head and neck cancers and colorectal cancer. 1
Cetuximab plus cisplatin/5-FU or carboplatin/5-FU improved median survival to 10.1 months versus 7.4 months with chemotherapy alone (P = 0.04) in the EXTREME trial of 442 patients with recurrent or metastatic squamous cell carcinoma. 1
Tyrosine Kinase Inhibitors
Gefitinib, erlotinib, and afatinib are standard-of-care for first-line treatment of EGFR-mutant advanced NSCLC, with proven benefits in response rate, progression-free survival, and quality of life over platinum-based chemotherapy. 1
Gefitinib reversibly inhibits the kinase activity of wild-type and certain activating mutations of EGFR, with binding affinity for EGFR exon 19 deletion or exon 21 L858R mutations higher than for wild-type EGFR. 3
Erlotinib reversibly inhibits EGFR kinase activity, with binding affinity for EGFR exon 19 deletion or exon 21 (L858R) mutations higher than for wild-type receptor. 6
Mechanism of Inhibition
EGFR inhibitors block phosphatidylinositol turnover and diacylglycerol formation, upregulate inhibitory proteins like cyclin-dependent kinase inhibitor p27, reduce MAPK expression and proliferation marker Ki67, resulting in abnormal cell maturation, growth arrest, increased apoptosis, and inflammatory response. 1, 7
Common Pitfalls and Caveats
Tumors without sensitizing EGFR mutations should not be treated with EGFR TKI in any line of therapy, as recent data demonstrate lack of efficacy. 1
The rare EGFR exon 20 insertion variant p.A763_Y764insFQEA is associated with TKI responsiveness, unlike most other exon 20 insertions, emphasizing the importance of knowing the specific sequence alteration. 1
Germline p.T790M is associated with familial lung cancer predisposition, so genetic counseling should be considered if identified prior to TKI exposure. 1
Cigarette smoking (a moderate CYP1A2 inducer) increases erlotinib clearance and decreases AUC by 64% in current smokers compared with former/never smokers, potentially requiring dose adjustment. 6