Epidermal growth factor receptor (EGFR) L858R (EGFR L858R)

The epidermal growth factor receptor (EGFR) L858R is a common activating point mutation in exon 21 of the EGFR gene, resulting in a leucine-to-arginine substitution at codon 858 in the kinase domain's activation loop, which enhances EGFR tyrosine kinase activity and downstream signaling for cell proliferation and survival. This mutation occurs in approximately 10-40% of non-small cell lung cancers (NSCLC), particularly adenocarcinomas in never-smokers, females, and Asians, driving oncogenesis through constitutive activation independent of ligand binding. Unlike wild-type EGFR, L858R-mutant tumors respond to EGFR tyrosine kinase inhibitors (TKIs) like osimertinib, afatinib, erlotinib, gefitinib, and dacomitinib as first-line therapy, though with inferior progression-free survival compared to exon 19 deletions. Resistance often develops via secondary T790M mutation, MET amplification, or other alterations, prompting combination strategies such as TKI plus chemotherapy or MET inhibitors. L858R tumors exhibit aggressive features like higher malignancy, increased CXCR4 expression promoting invasion and metastasis (e.g., leptomeningeal carcinomatosis), and frequent co-mutations in tumor suppressors, complicating therapy. As a validated therapeutic target, EGFR L858R guides precision medicine in advanced NSCLC, with FDA approvals for multiple TKIs and ongoing trials exploring novel combinations.

Other names

EGFR exon 21 L858R mutationex21 L858RL858R EGFR mutation

Tyrosine kinase inhibition (reversible or irreversible EGFR-TKIs block kinase domain activity), Combination therapy to overcome resistance (e.g., EGFR TKI + MET inhibitor for MET amplification, EGFR TKI + chemotherapy), Monoclonal antibody blockade (cetuximab inhibits ligand binding), Immune checkpoint inhibition (pembrolizumab for PD-L1 positive tumors post-TKI)