Epidermal growth factor receptor T790M mutation (EGFR T790M)

The epidermal growth factor receptor T790M mutation is a specific point mutation in the kinase domain of the epidermal growth factor receptor (EGFR), where threonine at position 790 is replaced by methionine. This alteration confers resistance to first-generation and second-generation EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib, erlotinib, and afatinib in patients with non-small cell lung cancer. The presence of this gatekeeper mutation increases ATP affinity within the mutant kinase domain, reducing inhibitor effectiveness. Third-generation TKIs—most notably osimertinib—were developed specifically to target this resistant form by irreversibly binding to a cysteine residue near the ATP-binding pocket. Detection of the T790M mutation via tissue biopsy or circulating tumor DNA serves as both a predictive biomarker for targeted therapy selection and an indicator of acquired drug resistance during treatment. While these therapies have improved outcomes for patients harboring this alteration, additional mutations can arise that confer further drug resistance, presenting ongoing therapeutic challenges.

Other names

EGFR T790MEpidermal growth factor receptor threonine 790 methionine mutationEGFR Thr790MetEGFR exon 20 T790M mutation

Irreversible inhibition of mutant kinase activity by covalent binding to C797 residue in the ATP-binding site (e.g., osimertinib)