Epidermal growth factor receptor (EGFR) T790M and other non-exon 20 insertion activating mutants (EGFR T790M/Activating Mutants)

The Epidermal Growth Factor Receptor (EGFR) is a transmembrane receptor tyrosine kinase that plays a critical role in cell signaling pathways governing growth, proliferation, and survival (Source: UniProt P00533). In certain cancers, particularly non-small cell lung cancer (NSCLC), the EGFR gene undergoes somatic mutations that lead to the constitutive activation of its kinase domain. The most common "sensitizing" mutations include deletions in exon 19 and the L858R point mutation in exon 21, which render the tumor highly sensitive to tyrosine kinase inhibitors (TKIs) (Source: NIH/NCI). However, clinical resistance often emerges through a secondary "gatekeeper" mutation, T790M, which increases the receptor's affinity for ATP and prevents first-generation TKIs from binding effectively (Source: PubMed PMC4454492). Third-generation TKIs have been developed to specifically and irreversibly target both the initial activating mutations and the T790M resistance mutation while maintaining high selectivity over wild-type EGFR. This selectivity helps minimize side effects associated with the inhibition of normal EGFR in healthy tissues, such as the skin and gastrointestinal tract (Source: FDA/Osimertinib Label). This specific target profile excludes exon 20 insertion mutations, which represent a distinct molecular subset of EGFR-mutant lung cancer with different structural requirements for drug binding (Source: PubMed PMC8153355).

Other names

HER1ErbB1EGFR sensitizing mutationsEGFR gatekeeper mutationEGFR T790MEGFR L858REGFR Exon 19 deletion

Irreversible (covalent) inhibition of the tyrosine kinase activity of mutant EGFR by binding to the cysteine 797 (C797) residue in the ATP-binding pocket, thereby blocking downstream oncogenic signaling pathways such as MAPK/ERK and PI3K/Akt (Source: PubMed PMC4454492, FDA/Osimertinib Label).