Epidermal growth factor receptor L718Q mutant (EGFR L718Q)

The Epidermal growth factor receptor (EGFR) L718Q mutant is a clinically significant variant of the EGFR protein that emerges as a mechanism of acquired resistance in non-small cell lung cancer (NSCLC) [amegroups.cn, nih.gov]. This mutation involves a substitution of leucine with glutamine at position 718 in the P-loop of the kinase domain, which is part of the ATP-binding pocket [nih.gov]. The L718Q mutation causes steric hindrance and alters the hydrophobic environment of the binding site, significantly reducing the efficacy of third-generation tyrosine kinase inhibitors (TKIs) such as osimertinib [nih.gov, researchgate.net]. It often co-occurs with the L858R sensitizing mutation and can lead to resistance against both first- and third-generation TKIs [aacrjournals.org, nih.gov]. Despite this resistance, some second-generation irreversible TKIs, such as afatinib and dacomitinib, have demonstrated the ability to inhibit the L718Q mutant in preclinical and clinical settings [nih.gov]. Identifying the L718Q mutation through next-generation sequencing or liquid biopsy is essential for tailoring subsequent therapeutic strategies for patients who have progressed on standard EGFR-targeted therapies [nih.gov, oncokb.org].

Other names

EGFR L718QEpidermal growth factor receptor L718QErbB-1 L718QHER1 L718QEGFR exon 18 L718Q mutation

Tyrosine kinase inhibitors (TKIs) target the EGFR L718Q mutant by binding to the adenosine triphosphate (ATP) binding site of the intracellular kinase domain, thereby blocking the phosphorylation of downstream signaling proteins and inhibiting cell proliferation [bocsci.com, nih.gov]. Second-generation TKIs like afatinib form irreversible covalent bonds with the receptor, which can sometimes overcome the steric hindrance caused by the L718Q mutation [nih.gov].