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

The Epidermal growth factor receptor (EGFR) L858R mutant is a specific oncogenic form of the EGFR protein, resulting from a leucine-to-arginine substitution at position 858 in exon 21 [1, 3, 10]. This point mutation occurs within the tyrosine kinase domain, leading to constitutive, ligand-independent activation of the receptor and its downstream signaling pathways, such as PI3K/AKT and MAPK/ERK [1, 3]. These pathways drive uncontrolled cell proliferation, survival, and metastasis, making the L858R mutation a critical driver in non-small cell lung cancer (NSCLC), particularly among non-smokers and East Asian populations [1, 2, 7]. As a therapeutic target, the L858R mutant is highly sensitive to various generations of tyrosine kinase inhibitors (TKIs), including gefitinib, erlotinib, and the third-generation inhibitor osimertinib [2, 6, 10]. However, clinical management is often challenged by the development of acquired resistance, most commonly through the secondary T790M mutation [6, 7, 8]. Targeted therapies have significantly improved survival outcomes for patients harboring this mutation, though they are associated with side effects like skin toxicity and gastrointestinal distress [4, 10].

Other names

ErbB-1 L858RHER1 L858REGFR exon 21 L858R mutationLeu858Arg

Tyrosine kinase inhibition (ATP-competitive or allosteric), blocking autophosphorylation and downstream signaling pathways such as PI3K/AKT and MAPK/ERK [1, 3, 6].