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

The Epidermal growth factor receptor (EGFR) L861Q is a specific point mutation located in exon 21 of the EGFR gene, characterized by the substitution of leucine with glutamine at position 861 (UniProt: P00533). This alteration is categorized as an "uncommon" or "atypical" mutation, accounting for roughly 2% of EGFR mutations in non-small cell lung cancer (NSCLC) (Myall et al., 2020). Functionally, the L861Q mutation induces conformational changes that result in the constitutive activation of the receptor's kinase domain, driving oncogenic signaling through the PI3K/Akt and MAPK/ERK pathways (Kobayashi et al., 2013). Clinically, tumors harboring the L861Q mutation exhibit varying degrees of sensitivity to tyrosine kinase inhibitors (TKIs); while they are less sensitive to first-generation TKIs like erlotinib, they show significant clinical response to second-generation irreversible inhibitors such as afatinib and third-generation inhibitors like osimertinib (Yang et al., 2015; Cho et al., 2020). Identifying this mutation through molecular testing is critical for selecting the most effective targeted therapy, as it dictates a different treatment strategy compared to common EGFR mutations like exon 19 deletions. Despite initial responses, therapeutic challenges include the eventual development of drug resistance and the management of off-target toxicities related to the inhibition of wild-type EGFR in healthy tissues.

Other names

ErbB1 L861QHER1 L861QEGFR Leu861GlnExon 21 L861Q mutation

Competitive inhibition of adenosine triphosphate (ATP) binding to the tyrosine kinase domain of the epidermal growth factor receptor, thereby blocking downstream signaling cascades (PubMed: 25589519).