Epidermal growth factor receptor (EGFR) with exon 19 deletion, T790M, and C797S mutations (EGFR E19del/T790M/C797S)

The Epidermal growth factor receptor (EGFR) with exon 19 deletion, T790M, and C797S mutations is a complex compound mutant that represents a major therapeutic challenge in advanced non-small cell lung cancer (NSCLC) [Leonetti et al., 2019]. This triple mutant typically evolves in patients who have progressed on sequential lines of therapy: starting with an activating exon 19 deletion, developing the T790M gatekeeper mutation after first-generation inhibitors, and finally acquiring the C797S mutation after treatment with third-generation inhibitors like osimertinib [Thress et al., 2015]. The C797S mutation occurs in the ATP-binding pocket, specifically abolishing the covalent bond that third-generation tyrosine kinase inhibitors (TKIs) rely on for potency [Wang et al., 2020]. Biologically, this mutant maintains constitutive activation of downstream signaling pathways, including MAPK and PI3K/AKT, which drive tumor cell proliferation and survival [Passaro et al., 2021]. Current drug development is focused on fourth-generation TKIs, such as BLU-945 and BBT-176, which are designed to inhibit the kinase activity of the triple mutant while sparing wild-type EGFR to minimize toxicity [Blueprint Medicines, 2021; Bridge Biotherapeutics, 2022]. Additionally, combination strategies involving antibodies like amivantamab or cetuximab are being explored to overcome this resistance by targeting the extracellular domain or promoting receptor degradation [Bauml et al., 2021].

Other names

EGFR triple mutantEGFR del19/T790M/C797SOsimertinib-resistant EGFR mutantEGFR compound mutant

Tyrosine kinase inhibition, Allosteric inhibition, Monoclonal antibody binding