Epidermal growth factor receptor (EGFR) exon 19 deletion and C797S double mutant (EGFR ex19del/C797S)

The Epidermal growth factor receptor (EGFR) exon 19 deletion/C797S double mutant is a clinically significant oncogenic variant primarily associated with non-small cell lung cancer (NSCLC) [1.1.1]. The exon 19 deletion is a common activating mutation that drives constitutive kinase activity, leading to uncontrolled cell proliferation and survival [1.1.1]. The C797S mutation typically emerges as an acquired resistance mechanism following treatment with third-generation tyrosine kinase inhibitors (TKIs) like osimertinib [1.1.2]. Because the C797 residue is the site of covalent attachment for these drugs, its mutation to serine (S) prevents the formation of the critical covalent bond, rendering standard third-generation therapies ineffective [1.1.4]. This double mutant represents a major therapeutic challenge and a critical unmet medical need, as it is resistant to all currently FDA-approved EGFR TKIs [1.2.1]. Research is currently focused on developing fourth-generation TKIs, including reversible and allosteric inhibitors, that can potently target the C797S variant while sparing wild-type EGFR to minimize toxicities such as skin rash and diarrhea [1.2.5].

Other names

EGFR del19/C797SEGFR E746_A750del/C797SEGFR exon 19 deletion/C797SEpidermal growth factor receptor exon 19 deletion and C797S double mutant

Inhibition of the EGFR tyrosine kinase domain through reversible or allosteric binding to overcome the loss of the C797 covalent attachment site.