Epidermal growth factor receptor (EGFR) C797X (EGFR C797X)

The Epidermal growth factor receptor (EGFR) C797X mutation, most frequently occurring as C797S, is a primary mechanism of acquired resistance in non-small cell lung cancer (NSCLC) patients treated with third-generation tyrosine kinase inhibitors (TKIs) like osimertinib (Thress et al., 2015, Nature Medicine). The mutation involves a substitution of the cysteine residue at position 797 within the ATP-binding pocket of the EGFR kinase domain, which is the critical site for covalent attachment of third-generation TKIs (Passaro et al., 2021, Cancer Cell). When this cysteine is mutated, the drugs can no longer form the covalent bond necessary for potent inhibition, leading to disease progression. This molecular alteration has prompted the development of fourth-generation EGFR TKIs and combination therapies, such as the use of brigatinib with cetuximab, to effectively target the receptor in the presence of C797X (Wang et al., 2020, Journal of Thoracic Oncology). The clinical impact of the mutation is also influenced by its allelic configuration; if C797S and the T790M gatekeeper mutation are in 'trans' (on different alleles), the tumor may remain sensitive to a combination of first- and third-generation TKIs, whereas a 'cis' configuration (on the same allele) presents a significant therapeutic challenge (Leonetti et al., 2019, British Journal of Cancer).

Other names

EGFR C797SEGFR C797GEGFR C797AErbB-1 C797XHER1 C797XEpidermal growth factor receptor C797S mutation

Inhibition of the tyrosine kinase activity of the epidermal growth factor receptor by binding to the ATP-binding pocket, specifically designed to overcome the loss of covalent binding caused by the C797X mutation.