Epidermal Growth Factor Receptor C797S (EGFR C797S)

The EGFR C797S mutation is a point mutation in the epidermal growth factor receptor where cysteine at position 797 is replaced by serine. This mutation is clinically significant as it emerges as a resistance mechanism in non-small-cell lung cancer patients treated with third-generation EGFR tyrosine kinase inhibitors such as osimertinib, CO-1686, and WZ4002. The C797S mutation is particularly problematic because third-generation EGFR inhibitors were designed to form covalent bonds with the cysteine at position 797. When this cysteine is replaced with serine, the covalent binding mechanism is disrupted, rendering these drugs ineffective. Structurally, the mutation increases local hydrophilicity around residue 797 without significantly altering the overall structure and function of the EGFR kinase. Current research is focused on developing fourth-generation EGFR inhibitors that can overcome this resistance mechanism. These include non-covalent inhibitors that don't rely on binding to position 797, allosteric inhibitors that target sites away from the ATP binding pocket, and combination therapies. Some promising approaches involve targeting hydrophobic regions of the EGFR kinase domain that remain unaffected by the C797S mutation. The C797S mutation often occurs in conjunction with other EGFR mutations, particularly the T790M mutation, creating complex resistance profiles that require sophisticated therapeutic strategies. Understanding the structural and functional implications of this mutation is crucial for developing effective treatments for patients with EGFR-mutated non-small-cell lung cancer who have developed resistance to current therapies.

Other names

EGFR T790M/C797S (when occurring with T790M mutation)C797S EGFR mutantCysteine-797 to Serine-797 EGFR mutation

The C797S mutation changes the nucleophilic cysteine C797 to the less reactive serine S797 in exon 20 of the EGFR tyrosine kinase domain. This mutation prevents the formation of covalent bonds between third-generation EGFR TKIs and the cysteine residue at position 797 in the ATP-binding pocket. Increases local hydrophilicity around residue 797 without significantly altering the structure and function of the EGFR kinase.