Epidermal growth factor receptor exon 19 deletion (E746-A750) (EGFR Δ746–750)

The Epidermal Growth Factor Receptor (EGFR) with the Δ746–750 mutation is a constitutively active mutant form of the receptor tyrosine kinase, characterized by an in-frame deletion of five amino acids (E746 through A750) in exon 19 [2, 4]. This mutation is the most common activating alteration in the EGFR gene, occurring in approximately 45-50% of EGFR-mutant non-small cell lung cancers (NSCLC) [2, 6]. The deletion causes a structural shift in the kinase domain's ATP-binding pocket, leading to ligand-independent activation of downstream signaling pathways such as RAS/MAPK, PI3K/Akt, and JAK/STAT [1, 11, 14]. These pathways drive critical oncogenic processes, including uncontrolled cell proliferation, survival, and angiogenesis [1, 13]. As a therapeutic target, EGFR Δ746–750 is highly sensitive to tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib, and osimertinib, which are the standard of care for patients harboring this mutation [3, 7, 12]. However, clinical management is often challenged by the development of acquired resistance, most notably the T790M "gatekeeper" mutation, which occurs in about 50-60% of patients treated with first-generation TKIs [8, 15]. Third-generation TKIs like osimertinib have been specifically designed to target both the primary activating mutation and the T790M resistance mutation [8, 19].

Other names

EGFR exon 19 deletiondelE746-A750EGFR ΔE746-A750ErbB1 Δ746-750HER1 Δ746-750EGFR-Ex19del

Inhibition of the epidermal growth factor receptor tyrosine kinase activity by competing with ATP (reversible inhibitors) or forming covalent bonds with the Cys797 residue (irreversible inhibitors) in the kinase domain [7, 8, 12].