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

The Epidermal growth factor receptor (EGFR) T790M mutant is a specific altered form of the EGFR protein, a receptor tyrosine kinase that plays a critical role in cell signaling pathways governing growth and survival (nih.gov, 1.1.3). This mutation, characterized by a threonine-to-methionine substitution at position 790, is famously known as the gatekeeper mutation because it frequently arises as an acquired resistance mechanism in non-small cell lung cancer (NSCLC) patients treated with first-generation or second-generation tyrosine kinase inhibitors (TKIs) (esmo.org, 1.2.1). Mechanistically, the T790M substitution increases the receptor's affinity for ATP, which prevents reversible inhibitors from effectively competing for the binding site (nih.gov, 1.1.2). To overcome this, third-generation TKIs like osimertinib were developed to selectively and irreversibly bind to the mutant receptor, typically via a covalent bond with the Cys797 residue (nih.gov, 1.2.3). Beyond acquired resistance, T790M can also exist as a rare germline mutation associated with hereditary lung cancer predisposition (nih.gov, 1.3.2). Monitoring for this mutation via liquid or tissue biopsy is a standard clinical practice to determine eligibility for subsequent targeted therapies (nih.gov, 1.4.4).

Other names

T790M mutationGatekeeper mutationEGFR Thr790MetEGFR exon 20 T790MSecondary EGFR mutation

Irreversible inhibition via covalent binding to the Cysteine 797 residue in the ATP-binding pocket, selectively targeting mutant forms of the receptor while sparing wild-type EGFR (nih.gov, 1.2.3).