Epidermal growth factor receptor (EGFR) T790M and activating mutants (EGFR)

The Epidermal Growth Factor Receptor (EGFR) is a transmembrane glycoprotein and a member of the ErbB family of receptor tyrosine kinases, which regulates essential cellular processes including growth, proliferation, and survival (UniProt P00533). In non-small cell lung cancer (NSCLC), specific 'activating' mutations such as Exon 19 deletions or the L858R point mutation in the kinase domain lead to ligand-independent signaling and tumor progression (Lynch et al., N Engl J Med, 2004). While first-generation inhibitors like erlotinib are initially effective, the T790M 'gatekeeper' mutation frequently emerges as a secondary resistance mechanism by increasing the receptor's affinity for ATP (Pao et al., Proc Natl Acad Sci U S A, 2005). Third-generation tyrosine kinase inhibitors (TKIs), such as osimertinib and lazertinib, are designed to selectively and irreversibly inhibit both the primary activating mutations and the T790M resistance mutation while sparing wild-type EGFR (Cross et al., Cancer Discov, 2014; J&J Press Release, 2024). This selectivity improves the therapeutic index by reducing toxicities associated with wild-type EGFR inhibition in healthy tissues, such as the skin and gastrointestinal tract (FDA Label: Tagrisso).

Other names

ErbB-1HER1Proto-oncogene c-ErbB-1EGFR T790MEGFR activating mutations

Irreversible inhibition of the EGFR tyrosine kinase domain through covalent binding to the Cys797 residue, effectively blocking signaling in the presence of T790M and activating mutants while maintaining selectivity over wild-type EGFR.