Epidermal growth factor receptor exon 21 L858R mutation (EGFR L858R)

The Epidermal growth factor receptor exon 21 L858R mutation is a *missense mutation* in the EGFR gene (T→G substitution at codon 858), resulting in a leucine-to-arginine substitution in the EGFR kinase domain's activation loop (A-loop) region[2][3][1]. This mutation destabilizes the inactive EGFR conformation, leading to *constitutive activation* of the receptor, increased dimerization, and enhanced downstream signaling that drives malignant phenotypes in NSCLC[1][3]. The L858R mutation is one of the two “classic” EGFR activating mutations (alongside exon 19 deletions), collectively accounting for ~90% of targetable EGFR variants in lung cancer[7]. EGFR-TKIs form the backbone of targeted therapy for EGFR L858R-mutant NSCLC, but clinical outcomes are typically somewhat less favorable compared with exon 19 deletion cases, prompting ongoing investigation into combination and next-generation strategies[1][5][4].

Other names

EGFR exon 21 L858RL858R mutationEGFR L858R variantEGFR Arg858 (Leu→Arg)

EGFR tyrosine kinase inhibition (reversible and irreversible) Inhibition of phosphorylation and downstream signaling Combination therapy with anti-angiogenic agents