Epidermal growth factor receptor (EGFR)

Epidermal growth factor receptor (EGFR) is a transmembrane protein belonging to the ErbB family of receptor tyrosine kinases. It is activated by ligand binding—primarily epidermal growth factor and transforming growth factor alpha—which induces dimerization and autophosphorylation on intracellular tyrosine residues. This triggers downstream signaling pathways including MAPK, Akt, and JNK cascades that regulate cell proliferation, survival, migration, adhesion, and DNA synthesis[3]. Mutations in the kinase domain—most notably "activating" mutations such as L858R or exon 19 deletions—render tumor cells highly sensitive to first-generation EGFR tyrosine kinase inhibitors (TKIs). However, most patients eventually develop resistance; approximately 60% acquire a secondary "gatekeeper" mutation at threonine 790 ("T790M"), which sterically hinders drug binding while preserving ATP affinity[2][6]. The presence of either an activating mutation or T790M defines a clinically actionable target for several generations of TKIs. Third-generation inhibitors like osimertinib are specifically designed to overcome T790M-mediated resistance by irreversibly inhibiting both sensitizing and resistant forms through covalent modification at cysteine 797 within the ATP-binding pocket[5]. Detection of these mutations serves as both a predictive biomarker for therapy selection and an indicator for monitoring disease progression or acquired resistance. Safety concerns include further emergence of tertiary resistance mutations such as C797S following prolonged inhibitor exposure[2]. The structural changes induced by these mutations alter drug sensitivity profiles; thus ongoing research focuses on structure-based design strategies targeting mutant-specific conformations within the kinase domain[1].

Other names

ErbB1HER1ERBBepidermal growth factor receptor tyrosine kinaseEGFR with activating mutation (e.g., L858R or exon 19 deletion)EGFR T790M mutant

Inhibition of tyrosine kinase activity by binding to the ATP-binding site of the mutated EGFR (including T790M and activating mutations) - Irreversible covalent binding to cysteine residue in the kinase domain (e.g., C797 for osimertinib)[5]