The Lifted Veil of Uncommon EGFR Mutation p.L747P in Non-Small Cell Lung Cancer: Molecular Feature and Targeting Sensitivity to Tyrosine Kinase Inhibitors

Abstract

ObjectivesThe uncommon p.L747P mutation in epidermal growth factor receptor (EGFR) exon 19 reveals to alter the response to tyrosine kinase inhibitors (TKIs) in patients diagnosed with advanced non-small cell lung cancer (NSCLC). However, the underlying mechanism is still not clear. This study aimed to investigate the clinical outcomes, binding affinities, and modes of action of currently available EGFR TKIs towards p.L747P mutation.Materials and MethodsClinical data of NSCLC patients harboring p.L747P mutation who had received different generations of EGFR TKIs were collected from medical records. Computational structure of p.L747P was constructed and in vitro cellular kinase inhibition assay and mice xenograft experiment were performed to predict and confirm the binding affinities and antitumor activities of diverse EGFR TKIs.ResultsA total of five metastatic NSCLC patients with p.L747P mutation were included in the final analysis. Patients treated with second-generation (2G) TKI afatinib achieved numerically longer progression-free survival (range 2.4-8.5 months) than that with first-generation (1G, range 1.4-5.5 months) or third-generation (3G, range 1.6-7.5 months) TKIs. None of the patients administered 1G or 3G TKIs achieved tumor response, but two-thirds of them treated with afatinib achieved partial response. Dynamics simulation predicted that 2G TKIs presented the best binding affinity to p.L747P mutation. The cellular kinase inhibition assay and mice xenograft experiment confirmed that afatinib could potently inhibit p.L747P-mutant cells and significantly reduce p.L747P-mutant tumor growth (P< 0.001), together with reduced phosphorylation of EGFR and its downstream signalings.ConclusionsThe uncommon p.L747P mutation in EGFR exon 19 resulted in a poor response to first-generation EGFR TKIs. Afatinib revealed a better clinical response and binding affinity compared with osimertinib for this specific alteration.