Epidermal growth factor receptor (EGFR) with exon 19 deletion or exon 21 L858R mutation and C797S resistance mutation (EGFR Ex19del/L858R + C797S)

The Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein that functions as a receptor tyrosine kinase, playing a vital role in signaling pathways that regulate cell growth, survival, and differentiation (Source: UniProt P00533). In non-small cell lung cancer (NSCLC), oncogenic drivers often include activating mutations such as deletions in exon 19 or the L858R point mutation in exon 21, which lead to constitutive activation of the kinase domain (Source: PubMed 15118125). While third-generation tyrosine kinase inhibitors (TKIs) like osimertinib are highly effective against these sensitizing mutations and the T790M resistance mutation, the C797S mutation frequently emerges as a secondary resistance mechanism (Source: Nature Medicine 21, 560–562). The C797S mutation involves a cysteine-to-serine substitution at position 797, which abolishes the covalent binding site required for the activity of irreversible third-generation TKIs (Source: Clinical Cancer Research 21, 3924-3933). This specific mutant profile—combining a sensitizing mutation with C797S—represents a significant therapeutic hurdle, as it renders most currently approved TKIs ineffective. Consequently, this molecular entity is the primary focus for the development of fourth-generation TKIs and bispecific antibodies designed to overcome C797S-mediated resistance (Source: Journal of Hematology & Oncology 15, 1-15). These novel agents aim to restore therapeutic control by binding to the ATP pocket of the receptor even in the absence of the cysteine residue. Clinical management of patients with this target often involves the use of liquid biopsies to monitor for the emergence of C797S in circulating tumor DNA (Source: PubMed 25974308). Furthermore, the allelic context of C797S (whether it occurs in cis or trans with other mutations) significantly influences the choice of subsequent therapy (Source: Nature Communications 8, 14768). Ongoing clinical trials are evaluating both monotherapies and combination regimens to address the complex signaling landscape created by these co-occurring mutations.

Other names

EGFR C797SEGFR triple mutantEGFR Ex19del/T790M/C797SEGFR L858R/T790M/C797SOsimertinib-resistant EGFREGFR C797S-positive NSCLCEGFR Ex19del/C797SEGFR L858R/C797S

Inhibition of the EGFR tyrosine kinase domain by binding to the ATP-binding pocket in a manner that does not require the C797 cysteine residue for efficacy, thereby blocking downstream oncogenic signaling.