2021
Lung Cancer Driven by BRAFG469V Mutation Is Targetable by EGFR Kinase Inhibitors
Huo K, Notsuda H, Fang Z, Liu N, Gebregiworgis T, Li Q, Pham N, Li M, Liu N, Shepherd F, Marshall C, Ikura M, Moghal N, Tsao M. Lung Cancer Driven by BRAFG469V Mutation Is Targetable by EGFR Kinase Inhibitors. Journal Of Thoracic Oncology 2021, 17: 277-288. PMID: 34648945, DOI: 10.1016/j.jtho.2021.09.008.Peer-Reviewed Original ResearchConceptsEGFR tyrosine kinase inhibitorsTyrosine kinase inhibitorsLung cancerBRAF mutationsNon-small cell lung cancerNon-V600 BRAF mutationsPatient-derived xenograft modelsKinase inhibitorsCell lung cancerEGFR-TKI gefitinibSingle-agent vemurafenibV600E BRAF mutationRNA knockdownCell linesExpression of BRAFOff-target inhibitionCombination dabrafenibTKI gefitinibTargeted therapyLung adenocarcinomaXenograft modelEGFR kinase inhibitorsPatientsOncogenic driversBRAF
2020
NMR in integrated biophysical drug discovery for RAS: past, present, and future
Marshall C, KleinJan F, Gebregiworgis T, Lee K, Fang Z, Eves B, Liu N, Gasmi-Seabrook G, Enomoto M, Ikura M. NMR in integrated biophysical drug discovery for RAS: past, present, and future. Journal Of Biomolecular NMR 2020, 74: 531-554. PMID: 32804298, DOI: 10.1007/s10858-020-00338-6.Peer-Reviewed Original ResearchConceptsGTPase domainProper membrane localizationMultiple signaling cascadesOncogenic Ras mutationsKey downstream effectorDrug discoveryGTPase cycleMembrane localizationRAS proteinsGTP hydrolysisConformational selectionRAS signalingDownstream effectorsSignaling cascadesLipid modificationG12C mutantUpstream regulatorBiophysical approachesSmall proteinsRAS oncogenesDruggable pocketHuman cancersCell growthCovalent inhibitorsPeptidyl inhibitorsMultivalent assembly of KRAS with the RAS-binding and cysteine-rich domains of CRAF on the membrane
Fang Z, Lee K, Huo K, Gasmi-Seabrook G, Zheng L, Moghal N, Tsao M, Ikura M, Marshall C. Multivalent assembly of KRAS with the RAS-binding and cysteine-rich domains of CRAF on the membrane. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 12101-12108. PMID: 32414921, PMCID: PMC7275734, DOI: 10.1073/pnas.1914076117.Peer-Reviewed Original ResearchConceptsRas-binding domainCysteine-rich domainC-terminusΑ4-α5Transient electrostatic interactionsLipid-binding siteCancer-associated mutationsMembrane interfaceKRAS dimerizationMembrane anchoringMembrane associationKinase domainRaf kinaseMembrane complexPlasma membraneStructural insightsKinase activityMAPK signalingTerminusComplex formationMembraneDynamic interactionDynamic pictureComplexesDomain