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.
Highlights
Lung cancer is the leading cause of cancer-related mortality worldwide
A cohort study conducted in Taiwan, China only identified 12 patients with the uncommon p.L747P or p.L747S mutations among 2031 epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LUAD) patients, which resulted in an overall incidence of approximately 0.59% [30]
The EGFR kinase 3D structure showed that condon 747 was located at the end of the b3 strand connecting to the C-helix
Summary
Lung cancer is the leading cause of cancer-related mortality worldwide. New strategies have been developed to target specific alterations in lung cancer in the last decade and improved treatment outcomes and survival [1]. Classic activating mutations of the epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) are found in approximately 47% of patients in Asian-Pacific countries [2] Most of these mutations occur in exons 18 to 21 of EGFR gene, which encode the main EGFR tyrosine kinase binding domain [3, 4]. Exon 19 deletion (19del) and exon 21 missense mutation L858R are the two most common activating forms, accounting for nearly 80% to 90% of the total EGFR mutations, which are strong predictors of favorable response to tyrosine kinase inhibitors (TKIs) and viewed as sensitizing EGFR alterations These mutations are most commonly seen in young Asian females diagnosed with lung adenocarcinoma (LUAD) who never smoked [5,6,7,8,9,10]
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