Epidermal growth factor receptor L858R (EGFR L858R)

The Epidermal growth factor receptor (EGFR) L858R is a common activating mutation located in exon 21 of the EGFR gene, resulting in a leucine-to-arginine substitution at codon 858 [1, 9]. This mutation is a primary oncogenic driver in non-small cell lung cancer (NSCLC), particularly in lung adenocarcinoma among non-smokers and East Asian populations [4, 15]. Structurally, the L858R mutation destabilizes the inactive state of the kinase domain, leading to constitutive, ligand-independent activation of downstream signaling pathways such as PI3K/AKT and RAS/RAF/MEK/ERK [2, 13]. These pathways promote uncontrolled cell growth, survival, and metastasis [1, 11]. Therapeutic strategies primarily involve small-molecule tyrosine kinase inhibitors (TKIs) like gefitinib, erlotinib, and osimertinib, which compete with ATP for binding to the mutated kinase domain [3, 5]. While initially highly effective, clinical challenges include the inevitable development of resistance mutations, most notably the T790M gatekeeper mutation and the C797S mutation [10, 14]. Recent research also suggests that L858R-mutant EGFR is uniquely dependent on receptor dimerization, potentially making it susceptible to dimerization-inhibitory antibodies like cetuximab [7, 12].

Other names

EGFR L858R activating mutantEpidermal growth factor receptor exon 21 L858R mutationErbB1 L858RHER1 L858RLeucine 858 to Arginine mutation

Tyrosine kinase inhibition via competitive binding to the ATP-binding site of the mutated kinase domain; inhibition of receptor dimerization (for monoclonal antibodies).