Epidermal growth factor receptor C797S and other C797X mutants (EGFR C797S/X)

The Epidermal Growth Factor Receptor (EGFR) is a transmembrane receptor tyrosine kinase that regulates essential cellular processes including proliferation, survival, and differentiation [1.2.2, 1.4.2]. In the context of non-small cell lung cancer (NSCLC), EGFR mutations serve as primary oncogenic drivers [1.1.1, 1.2.5]. While third-generation EGFR tyrosine kinase inhibitors (TKIs) like osimertinib are highly effective against sensitizing and T790M resistance mutations, the acquisition of the C797S mutation is a frequent cause of treatment failure [1.1.2, 1.4.1]. This mutation involves the substitution of the cysteine residue at position 797, which is the critical site for covalent attachment of third-generation inhibitors, with serine or other amino acids (C797X) [1.5.1, 1.5.2]. Consequently, these drugs lose their inhibitory potency, necessitating the development of fourth-generation TKIs [1.2.1, 1.4.3]. These next-generation agents, including allosteric and non-covalent inhibitors, aim to overcome resistance by binding to the mutated kinase domain through alternative mechanisms, often in combination with other therapies to prevent further bypass resistance [1.1.3, 1.5.3].

Other names

EGFR C797SEGFR C797XEGFR Cys797SerEGFR Cys797GlyEpidermal growth factor receptor C797S mutationEGFR triple mutant

Fourth-generation EGFR tyrosine kinase inhibitors (TKIs) target C797S/X mutants through non-covalent ATP-competitive inhibition or allosteric modulation, bypassing the requirement for the cysteine 797 residue for binding [1.1.1, 1.2.1].