2024
ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts.
Hu B, Wiesehöfer M, de Miguel F, Liu Z, Chan L, Choi J, Melnick M, Arnal Estape A, Walther Z, Zhao D, Lopez-Giraldez F, Wurtz A, Cai G, Fan R, Gettinger S, Xiao A, Yan Q, Homer R, Nguyen D, Politi K. ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts. Cancer Research 2024, 84: 1303-1319. PMID: 38359163, DOI: 10.1158/0008-5472.can-23-0438.Peer-Reviewed Original ResearchTyrosine kinase inhibitorsPatient-derived xenograftsEGFR mutant lung cancerMutant lung cancerPre-treatment tumorsResidual diseaseDrug toleranceLung cancerResidual tumor cells in vivoEGFR mutant lung adenocarcinomaTyrosine kinase inhibitor osimertinibEGFR tyrosine kinase inhibitorsTyrosine kinase inhibitor treatmentTumor cells in vivoMutant lung adenocarcinomaMaximal tumor regressionTranscription factor Ascl1Drug-tolerant cellsTime of maximal responseEvidence of cellsCells in vivoOsimertinib treatmentTumor regressionSingle cell transcriptional profilingTumor cells
2020
Drug Sensitivity and Allele Specificity of First-Line Osimertinib Resistance EGFR Mutations
Starrett JH, Guernet AA, Cuomo ME, Poels KE, van Alderwerelt van Rosenburgh IK, Nagelberg A, Farnsworth D, Price KS, Khan H, Ashtekar KD, Gaefele M, Ayeni D, Stewart TF, Kuhlmann A, Kaech S, Unni AM, Homer R, Lockwood WW, Michor F, Goldberg SB, Lemmon MA, Smith PD, Cross D, Politi K. Drug Sensitivity and Allele Specificity of First-Line Osimertinib Resistance EGFR Mutations. Cancer Research 2020, 80: 2017-2030. PMID: 32193290, PMCID: PMC7392201, DOI: 10.1158/0008-5472.can-19-3819.Peer-Reviewed Original ResearchConceptsOsimertinib resistancePreferred first-line therapyThird-generation EGFR tyrosine kinase inhibitorEGFR tyrosine kinase inhibitorsResistance EGFR mutationsFirst-line therapyMutant lung cancerFirst-line osimertinibSubsequent treatment approachesTransgenic mouse modelTyrosine kinase inhibitorsSecondary mutationsErlotinib treatmentLung cancerEGFR mutationsLung adenocarcinomaMouse modelTherapeutic strategiesTherapeutic testingTreatment approachesMutant tumorsResistance mutationsDrug sensitivityDriver mutationsKinase inhibitorsDrug Sensitivity and Allele‐specificity of First‐line Osimertinib Resistance EGFR Mutations
Starrett J, Guernet A, Cuomo M, Poels K, van Rosenburgh I, Nagelberg A, Farnsworth D, Price K, Khan H, Ashtekar K, Gaefele M, Ayeni D, Stewart T, Kuhlmann A, Kaech S, Unni A, Homer R, Lockwood W, Michor F, Goldberg S, Lemmon M, Smith P, Cross D, Politi K. Drug Sensitivity and Allele‐specificity of First‐line Osimertinib Resistance EGFR Mutations. The FASEB Journal 2020, 34: 1-1. DOI: 10.1096/fasebj.2020.34.s1.00612.Peer-Reviewed Original ResearchFirst-line osimertinibEGFR-mutant lung cancerMutant lung cancerOsimertinib treatmentEGFR-TKILung cancerEGFR mutationsTotal tumorsPreferred first-line therapySecondary mutationsThird-generation EGFR-TKIFirst-line osimertinib treatmentMichael Smith FoundationResistance EGFR mutationsFirst-line therapySecondary EGFR mutationGeneration EGFR-TKISubsequent treatment approachesTransgenic mouse modelLung cancer researchTumor volume changesCoronal MR imagesTumor volume measurementsNew Investigator AwardResistance mechanisms
2019
Tumor regression mediated by oncogene withdrawal or erlotinib stimulates infiltration of inflammatory immune cells in EGFR mutant lung tumors
Ayeni D, Miller B, Kuhlmann A, Ho PC, Robles-Oteiza C, Gaefele M, Levy S, de Miguel FJ, Perry C, Guan T, Krystal G, Lockwood W, Zelterman D, Homer R, Liu Z, Kaech S, Politi K. Tumor regression mediated by oncogene withdrawal or erlotinib stimulates infiltration of inflammatory immune cells in EGFR mutant lung tumors. Journal For ImmunoTherapy Of Cancer 2019, 7: 172. PMID: 31291990, PMCID: PMC6617639, DOI: 10.1186/s40425-019-0643-8.Peer-Reviewed Original ResearchConceptsTyrosine kinase inhibitorsEGFR-mutant lung cancerMutant lung cancerTumor regressionErlotinib treatmentLung cancerImmune cellsLung tumorsMouse modelEffects of TKIsGrowth factor receptor tyrosine kinase inhibitorsTumor-infiltrating immune cellsDrug resistanceReceptor tyrosine kinase inhibitorsInflammatory immune cellsInflammatory T cellsEffect of erlotinibEGFR mutant lung tumorsInflammatory cellsImmunological profileT cellsCD40 agonistsImmunostimulatory effectsAlveolar macrophagesErlotinib
2016
Afatinib plus Cetuximab Delays Resistance Compared to Single-Agent Erlotinib or Afatinib in Mouse Models of TKI-Naïve EGFR L858R-Induced Lung Adenocarcinoma
Pirazzoli V, Ayeni D, Meador CB, Sanganahalli BG, Hyder F, de Stanchina E, Goldberg SB, Pao W, Politi K. Afatinib plus Cetuximab Delays Resistance Compared to Single-Agent Erlotinib or Afatinib in Mouse Models of TKI-Naïve EGFR L858R-Induced Lung Adenocarcinoma. Clinical Cancer Research 2016, 22: 426-435. PMID: 26341921, PMCID: PMC4715986, DOI: 10.1158/1078-0432.ccr-15-0620.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinomaAdenocarcinoma of LungAfatinibAnimalsCell Line, TumorCetuximabDrug Evaluation, PreclinicalDrug Resistance, NeoplasmDrug Therapy, CombinationErbB ReceptorsErlotinib HydrochlorideLung NeoplasmsMiceMice, NudeMutationNeoplasm Recurrence, LocalProtein Kinase InhibitorsProtein-Tyrosine KinasesProto-Oncogene Proteins p21(ras)QuinazolinesConceptsTyrosine kinase inhibitorsLung adenocarcinomaLung cancerMouse modelAdvanced EGFR-mutant lung adenocarcinomaFirst-generation tyrosine kinase inhibitorSingle-agent tyrosine kinase inhibitorsEGFR-mutant lung cancerEGFR-mutant lung adenocarcinomaEGFR tyrosine kinase inhibitorsCetuximab-resistant tumorsPotential of afatinibFirst-line therapyMutant lung cancerEGFR antibody cetuximabCombination of afatinibEGFR-TKI afatinibClinical trial developmentEffective treatment strategiesDrug-resistant tumorsAgent erlotinibTKI-naïveAfatinib treatmentTumor escapeClinical trials
2014
Dual Inhibition of EGFR with Afatinib and Cetuximab in Kinase Inhibitor–Resistant EGFR-Mutant Lung Cancer with and without T790M Mutations
Janjigian YY, Smit EF, Groen HJ, Horn L, Gettinger S, Camidge DR, Riely GJ, Wang B, Fu Y, Chand VK, Miller VA, Pao W. Dual Inhibition of EGFR with Afatinib and Cetuximab in Kinase Inhibitor–Resistant EGFR-Mutant Lung Cancer with and without T790M Mutations. Cancer Discovery 2014, 4: 1036-1045. PMID: 25074459, PMCID: PMC4155006, DOI: 10.1158/2159-8290.cd-14-0326.Peer-Reviewed Original ResearchConceptsEGFR-mutant lung cancerT790M mutationLung cancerM mutationGrade 3/4 adverse eventsMedian progression-free survivalEGFR T790M mutationErlotinib/gefitinibRobust clinical activityT790M-negative tumorsManageable safety profileObjective response ratePhase Ib studyProgression-free survivalMutant lung cancerGefitinib/erlotinibFirst clinical proofReversible EGFR inhibitorsAdverse eventsMedian durationObjective responseSafety profilePreclinical hypothesisEGFR mutationsClinical activity
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