Epidermal growth factor receptor (EGFR) C797S mutant (EGFR C797S)

The Epidermal growth factor receptor (EGFR) C797S mutant is a tertiary resistance mutation that arises in patients with non-small cell lung cancer (NSCLC) following treatment with third-generation tyrosine kinase inhibitors (TKIs) like osimertinib. The mutation involves the substitution of cysteine at position 797 with serine in the ATP-binding pocket of the EGFR kinase domain. This specific cysteine residue is the site where third-generation irreversible TKIs form a covalent bond; its loss prevents these drugs from binding effectively, leading to disease progression. The C797S mutation often occurs alongside primary activating mutations (e.g., Exon 19 deletion or L858R) and the secondary T790M gatekeeper mutation. Therapeutic strategies to overcome this resistance include the development of fourth-generation TKIs, which may be ATP-competitive reversible inhibitors or allosteric inhibitors that do not rely on the C797 residue for binding. The clinical management of C797S-positive tumors is further complicated by the allelic configuration of the mutations, as those in trans (on different alleles) may respond to combinations of first- and third-generation TKIs, while those in cis (on the same allele) remain highly resistant to current standard therapies.

Other names

EGFR C797SEpidermal growth factor receptor C797S mutationErbB1 C797SEGFR Cys797SerEGFR triple mutant

Tyrosine kinase inhibition (targeting the ATP-binding site or allosteric sites to bypass the loss of the C797 covalent binding site)