Epidermal growth factor receptor (EGFR) T790M mutation (EGFR T790M)

The Epidermal growth factor receptor (EGFR) T790M mutation is a specific "gatekeeper" alteration in the kinase domain of the EGFR protein, characterized by the substitution of threonine with methionine at position 790. This mutation is the most common mechanism of acquired resistance in patients with non-small cell lung cancer (NSCLC) who have been treated with first- or second-generation tyrosine kinase inhibitors (TKIs) like gefitinib or erlotinib. Biologically, the T790M mutation increases the receptor's affinity for ATP, which prevents reversible inhibitors from effectively competing for the binding site. Third-generation TKIs, such as osimertinib, were developed to overcome this resistance by forming a covalent bond with the Cys797 residue in the ATP-binding pocket, thereby irreversibly inhibiting the mutant receptor. While these drugs are highly effective against T790M-positive tumors, they are designed to spare wild-type EGFR to minimize side effects like skin rash and diarrhea. The detection of T790M via tissue or liquid biopsy is a standard clinical practice to guide the transition to third-generation therapies. However, the emergence of further mutations, such as C797S, remains a significant therapeutic challenge in managing resistant disease.

Other names

ErbB-1 T790MHER1 T790MGatekeeper mutationThr790MetEGFR exon 20 T790M mutation

Irreversible covalent inhibition of the mutant EGFR kinase domain by binding to the Cys797 residue, overcoming the increased ATP affinity caused by the gatekeeper mutation.