Epidermal growth factor receptor (EGFR) with sensitizing and C797S resistance mutations (EGFRm+/C797S)

The Epidermal growth factor receptor (EGFR) with sensitizing and C797S resistance mutations is a specific variant of the EGFR protein that drives progression in non-small cell lung cancer (NSCLC) after treatment with third-generation inhibitors. The C797S mutation occurs in the kinase domain, where the cysteine residue at position 797 is replaced by serine, thereby preventing the covalent binding of drugs like osimertinib (Source: PubMed, PMID: 25974308). This mutation is often found alongside primary sensitizing mutations, such as Exon 19 deletions or the L858R point mutation, and frequently co-occurs with the T790M gatekeeper mutation (Source: Journal of Thoracic Oncology, 2021). Because the C797 residue is the essential site of attachment for irreversible inhibitors, its loss renders the receptor resistant to all currently FDA-approved EGFR tyrosine kinase inhibitors (TKIs) (Source: Nature Reviews Cancer, 2017). Current drug development efforts are focused on fourth-generation TKIs and allosteric inhibitors designed to bind effectively to the C797S mutant form while sparing wild-type EGFR (Source: Journal of Hematology & Oncology, 2022). These novel agents, such as BLU-945 and BBT-176, aim to overcome the steric and chemical hurdles posed by the serine substitution (Source: ClinicalTrials.gov). Clinical management of these mutants often involves monitoring through liquid biopsies to detect the emergence of C797S in circulating tumor DNA (Source: NIH/NCI). Understanding the orientation of C797S relative to T790M is also crucial, as it dictates the potential efficacy of combination therapies (Source: Cancer Discovery, 2020). Overall, this target represents the next frontier in precision oncology for EGFR-mutant lung cancer.

Other names

EGFR C797SEGFR triple mutantErbB1 C797SEGFR T790M/C797SEGFR exon 19 del/T790M/C797SEGFR L858R/T790M/C797S

Fourth-generation tyrosine kinase inhibition (reversible or allosteric) targeting the ATP-binding site or an adjacent pocket to bypass the loss of the C797 covalent bond (Source: ACS Medicinal Chemistry Letters).