File Download
  Links for fulltext
     (May Require Subscription)
Supplementary

Article: Prediction of sensitivity to gefitinib/erlotinib for EGFR mutations in NSCLC based on structural interaction fingerprints and multilinear principal component analysis

TitlePrediction of sensitivity to gefitinib/erlotinib for EGFR mutations in NSCLC based on structural interaction fingerprints and multilinear principal component analysis
Authors
KeywordsEpidermal growth factor receptor mutation
Interaction fingerprints
Molecular dynamics simulations
Multilinear principal component analysis
Issue Date2018
PublisherBioMed Central Ltd. The Journal's web site is located at http://www.biomedcentral.com/bmcbioinformatics/
Citation
BMC Bioinformatics, 2018, v. 19 n. 1, p. 88 How to Cite?
AbstractBACKGROUND: Non-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. RESULTS: To 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. CONCLUSIONS: We 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.
Persistent Identifierhttp://hdl.handle.net/10722/258363
ISSN
2017 Impact Factor: 2.213
2015 SCImago Journal Rankings: 1.722
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorZou, B-
dc.contributor.authorLee, VHF-
dc.contributor.authorYan, H-
dc.date.accessioned2018-08-22T01:37:17Z-
dc.date.available2018-08-22T01:37:17Z-
dc.date.issued2018-
dc.identifier.citationBMC Bioinformatics, 2018, v. 19 n. 1, p. 88-
dc.identifier.issn1471-2105-
dc.identifier.urihttp://hdl.handle.net/10722/258363-
dc.description.abstractBACKGROUND: Non-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. RESULTS: To 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. CONCLUSIONS: We 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.-
dc.languageeng-
dc.publisherBioMed Central Ltd. The Journal's web site is located at http://www.biomedcentral.com/bmcbioinformatics/-
dc.relation.ispartofBMC Bioinformatics-
dc.rightsBMC Bioinformatics. Copyright © BioMed Central Ltd.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectEpidermal growth factor receptor mutation-
dc.subjectInteraction fingerprints-
dc.subjectMolecular dynamics simulations-
dc.subjectMultilinear principal component analysis-
dc.titlePrediction of sensitivity to gefitinib/erlotinib for EGFR mutations in NSCLC based on structural interaction fingerprints and multilinear principal component analysis-
dc.typeArticle-
dc.identifier.emailLee, VHF: vhflee@hku.hk-
dc.identifier.authorityLee, VHF=rp00264-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1186/s12859-018-2093-6-
dc.identifier.pmid29514601-
dc.identifier.pmcidPMC5842518-
dc.identifier.hkuros286428-
dc.identifier.volume19-
dc.identifier.issue1-
dc.identifier.spage88-
dc.identifier.epage88-
dc.identifier.isiWOS:000427154900002-
dc.publisher.placeUnited Kingdom-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats