Epidermal growth factor receptor (EGFR) L861Q mutant (EGFR L861Q)

The Epidermal growth factor receptor (EGFR) L861Q mutant is an uncommon activating mutation located in exon 21 of the EGFR gene, involving a substitution of leucine with glutamine at position 861 (PMID: 17177598). This mutation occurs within the activation loop of the kinase domain, where the replacement of a hydrophobic residue with a polar one triggers a conformational shift to an active state, leading to constitutive, ligand-independent signaling (PMID: 25822522). This aberrant signaling drives oncogenic processes such as uncontrolled cell proliferation and survival, primarily in non-small cell lung cancer (NSCLC), where it represents approximately 2% of all EGFR mutations (PMID: 26051236). Clinically, the L861Q variant is categorized as an atypical or uncommon mutation because it shows a different sensitivity profile to tyrosine kinase inhibitors (TKIs) compared to common mutations like L858R. While it is less responsive to first-generation TKIs such as gefitinib and erlotinib, it demonstrates significant sensitivity to second-generation (afatinib) and third-generation (osimertinib) inhibitors (PMID: 31825714). Afatinib is specifically FDA-approved for the treatment of NSCLC patients harboring this mutation. Therapeutic challenges include the eventual development of acquired resistance, which may arise through secondary mutations like T790M or L718Q/V, necessitating ongoing molecular monitoring (PMID: 39421545).

Other names

ERBB1 L861QHER1 L861QEGFR p.Leu861GlnEGFR p.L861QEpidermal growth factor receptor L861Q

Tyrosine kinase inhibition via competitive binding to the ATP-binding site; second- and third-generation inhibitors like afatinib and osimertinib bind irreversibly to the Cys-797 residue (PMID: 27226600).