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

The Epidermal Growth Factor Receptor (EGFR) is a transmembrane receptor tyrosine kinase belonging to the ErbB family, which plays a vital role in signaling pathways that govern cell growth, proliferation, and survival (NIH). In non-small cell lung cancer (NSCLC), oncogenic mutations in the EGFR kinase domain, such as exon 19 deletions or the L858R substitution, lead to constitutive activation and drive tumor progression (ESMO). The T790M mutation is a secondary "gatekeeper" mutation in exon 20 that arises in approximately 50-60% of patients as a mechanism of acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) (Yun et al., 2008). This specific mutation involves the substitution of threonine with a bulky methionine residue at position 790, which increases the receptor's affinity for ATP, thereby reducing the potency of ATP-competitive reversible inhibitors (PNAS). Third-generation TKIs, such as osimertinib, were engineered to overcome this resistance by forming an irreversible covalent bond with the Cys797 residue in the ATP-binding pocket (J. Med. Chem.). These drugs effectively inhibit the T790M mutant while sparing wild-type EGFR, thus improving the therapeutic window and patient outcomes in resistant NSCLC (NIH). However, clinical challenges remain, including the emergence of tertiary resistance mutations like C797S and side effects such as interstitial lung disease and skin toxicity (J. Med. Chem.).

Other names

ErbB1 T790MHER1 T790MGatekeeper mutationEGFR exon 20 T790M

Irreversible covalent inhibition of the EGFR kinase domain by binding to the Cys797 residue, which overcomes the increased ATP affinity conferred by the T790M gatekeeper mutation (Yun et al., 2008; NIH).