Epidermal growth factor receptor (EGFR) with exon 19 deletion, Thr790Met, and Cys797Ser mutations (EGFR del19/T790M/C797S)

The Epidermal Growth Factor Receptor (EGFR) with exon 19 deletion, Thr790Met, and Cys797Ser mutations is a triple-mutant form of the receptor tyrosine kinase that drives resistance in non-small cell lung cancer (NSCLC) (Thress et al., Nature Medicine, 2015). The exon 19 deletion is a primary oncogenic driver, while the Thr790Met mutation is a secondary gatekeeper mutation that confers resistance to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) (UniProt P00533). The Cys797Ser mutation is a tertiary mutation that arises following treatment with third-generation TKIs like osimertinib, preventing the drug from forming a critical covalent bond with the cysteine residue at position 797 (Wang et al., Journal of Hematology & Oncology, 2021). This specific combination of mutations renders the receptor resistant to all currently FDA-approved EGFR TKIs, creating an urgent need for fourth-generation inhibitors (Lu et al., Frontiers in Oncology, 2022). These novel agents, such as BLU-945 and BBT-176, are designed to bind the ATP-binding pocket through non-covalent interactions or alternative mechanisms that bypass the Cys797Ser-mediated resistance (ClinicalTrials.gov, NCT04862780). Clinical development of these inhibitors focuses on achieving high potency against the triple mutant while maintaining selectivity over wild-type EGFR to minimize systemic toxicities such as skin rash and diarrhea.

Other names

EGFR triple mutantEGFR del19/T790M/C797SEGFR-DTCEpidermal growth factor receptor exon 19 deletion/T790M/C797S

Fourth-generation tyrosine kinase inhibition targeting the ATP-binding site of mutated EGFR