Abstract
BackgroundNon-small cell lung cancer (NSCLC) with activating EGFR mutations, especially exon 19 deletions and the L858R point mutation, is particularly responsive to gefitinib and erlotinib. However, the sensitivity varies for less common and rare EGFR mutations. There are various explanations for the low sensitivity of EGFR exon 20 insertions and the exon 20 T790 M point mutation to gefitinib/erlotinib. However, few studies discuss, from a structural perspective, why less common mutations, like G719X and L861Q, have moderate sensitivity to gefitinib/erlotinib.ResultsTo decode the drug sensitivity/selectivity of EGFR mutants, it is important to analyze the interaction between EGFR mutants and EGFR inhibitors. In this paper, the 30 most common EGFR mutants were selected and the technique of protein-ligand interaction fingerprint (IFP) was applied to analyze and compare the binding modes of EGFR mutant-gefitinib/erlotinib complexes. Molecular dynamics simulations were employed to obtain the dynamic trajectory and a matrix of IFPs for each EGFR mutant-inhibitor complex. Multilinear Principal Component Analysis (MPCA) was applied for dimensionality reduction and feature selection. The selected features were further analyzed for use as a drug sensitivity predictor. The results showed that the accuracy of prediction of drug sensitivity was very high for both gefitinib and erlotinib. Targeted Projection Pursuit (TPP) was used to show that the data points can be easily separated based on their sensitivities to gefetinib/erlotinib.ConclusionsWe can conclude that the IFP features of EGFR mutant-TKI complexes and the MPCA-based tensor object feature extraction are useful to predict the drug sensitivity of EGFR mutants. The findings provide new insights for studying and predicting drug resistance/sensitivity of EGFR mutations in NSCLC and can be beneficial to the design of future targeted therapies and innovative drug discovery.
Highlights
Non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations, especially exon 19 deletions and the L858R point mutation, is responsive to gefitinib and erlotinib
Our results showed that the accuracy of prediction of drug sensitivity was very high for both gefitinib and erlotinib
EGFR mutation selection EGFR mutations were selected according to the survey carried out in [49] and were the 11 most common exon deletions, the 6 most common exon insertions, the most common exon deletion delE709_T710insD, the most common exon insertion I744_K745insKIPVAI, G719X (A, C or S), E709X (A or K), S761I, L858R, L861Q and T790 M (Table 1)
Summary
Non-small cell lung cancer (NSCLC) with activating EGFR mutations, especially exon 19 deletions and the L858R point mutation, is responsive to gefitinib and erlotinib. Somatic mutations in the kinase domain of the epidermal growth factor receptor (EGFR) gene are detected in about 10–35% of patients with advanced non-small cell lung cancer (NSCLC) [1,2,3]. These mutations occur within EGFR exons 18–21 and more than 80% of them are exon 19 deletions or the exon 21 L858R point mutation [4, 5]. Some other less common mutations, like exon 18 point mutations in position G719 (G719A, C or S, about 3% of all tumors) and the exon 21 L861Q mutation (about 2% of all tumors), are associated with some level of sensitivity to gefitinib/erlotinib [1, 4, 21,22,23,24,25,26,27,28,29,30]
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