Epidermal growth factor receptor L858R mutant kinase (EGFR L858R)

Epidermal growth factor receptor L858R mutant kinase refers to a specific activating point mutation (substitution of leucine to arginine at amino acid 858) within the kinase domain of the human epidermal growth factor receptor (EGFR), a transmembrane receptor tyrosine kinase. This mutation is one of the most common oncogenic drivers in non-small cell lung cancer (NSCLC), accounting for ~40% of all activating EGFR mutations in NSCLC. The L858R mutation destabilizes the inactive conformation and preferentially stabilizes the active conformation of the kinase, rendering signaling independent of ligand binding and promoting constitutive downstream pathway activation[2][3][1]. This enhances cell proliferation and survival, contributing to oncogenic transformation. Tumors harboring the EGFR L858R mutation are highly sensitive to several classes of EGFR tyrosine kinase inhibitors (TKIs), including both first-generation (erlotinib, gefitinib), second-generation (afatinib, dacomitinib), and third-generation inhibitors (osimertinib)[4][6]. Resistance can develop, most notably through the emergence of the T790M secondary mutation. Detection of the L858R mutation serves as a predictive biomarker for TKI response and is fundamental for personalizing therapy in NSCLC patients. Irreversible and radiolabeled inhibitors can also selectively bind and image tumors carrying this mutation[4]. Treatment is associated with both class-specific and mutation-specific challenges, including resistance and characteristic adverse effects.

Other names

EGFR L858R mutantEGFR L858RL858R-mutant EGFRL858R mutation of EGFREpidermal growth factor receptor L858R

Competitive inhibition of ATP binding to mutant kinase domain Irreversible (covalent) inhibition of kinase Allosteric inhibition Induction of receptor degradation