Epidermal growth factor receptor (EGFR) T790M and activating mutations (EGFR T790M/Activating Mutations)

The Epidermal Growth Factor Receptor (EGFR) is a transmembrane receptor tyrosine kinase that regulates essential cellular processes including proliferation, survival, and differentiation (Onclive, 2021). In non-small cell lung cancer (NSCLC), "activating" mutations such as exon 19 deletions and the L858R point mutation cause constitutive receptor signaling, driving tumor growth (NIH, 2009). While these mutations initially respond to first-generation inhibitors like gefitinib, resistance typically emerges via the T790M "gatekeeper" mutation, which increases the receptor's affinity for ATP and prevents inhibitor binding (Harvard, 2008; ESMO, 2019). Third-generation tyrosine kinase inhibitors (TKIs), such as osimertinib and lazertinib, were developed to irreversibly bind to the EGFR kinase domain containing both activating and T790M mutations while sparing the wild-type receptor (Cancer.gov, 2019; J&J, 2024). These agents effectively block downstream signaling pathways, such as MAPK and PI3K/Akt, leading to apoptosis in mutant-bearing cancer cells (AACR, 2015). Clinical use of these inhibitors has significantly improved progression-free survival in patients with T790M-positive NSCLC, though monitoring for toxicities like interstitial lung disease and QT prolongation remains necessary (Lungevity, 2024; NIH, 2017).

Other names

EGFR T790MEGFR exon 19 deletionEGFR L858REGFR sensitizing mutationsEGFR gatekeeper mutationHER1ERBB1

Irreversible inhibition of the EGFR tyrosine kinase domain by covalent binding to the C797 residue, blocking ATP binding and downstream signaling in mutated forms of the receptor.