2016
Oncogenic EGFR Represses the TET1 DNA Demethylase to Induce Silencing of Tumor Suppressors in Cancer Cells
Forloni M, Gupta R, Nagarajan A, Sun LS, Dong Y, Pirazzoli V, Toki M, Wurtz A, Melnick MA, Kobayashi S, Homer RJ, Rimm DL, Gettinger SJ, Politi K, Dogra SK, Wajapeyee N. Oncogenic EGFR Represses the TET1 DNA Demethylase to Induce Silencing of Tumor Suppressors in Cancer Cells. Cell Reports 2016, 16: 457-471. PMID: 27346347, PMCID: PMC4945411, DOI: 10.1016/j.celrep.2016.05.087.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinomaAdenocarcinoma of LungAntineoplastic AgentsBrain NeoplasmsCCAAT-Enhancer-Binding ProteinsCell Line, TumorCpG IslandsDNA MethylationDrug Screening Assays, AntitumorErbB ReceptorsGene Expression Regulation, NeoplasticGene SilencingGlioblastomaHumansLung NeoplasmsMAP Kinase Signaling SystemMixed Function OxygenasesMutationOncogenesProtein Kinase InhibitorsProto-Oncogene ProteinsTranscription, GeneticTumor Suppressor ProteinsUp-RegulationConceptsOncogenic epidermal growth factor receptorMethylation-mediated transcriptional silencingEpidermal growth factor receptorTumor suppressorTranscriptional silencingActive DNA demethylationCancer cellsFamily member 1TET1 knockdownDNA demethylaseDNA demethylationTranscription factorsGrowth factor receptorEctopic expressionCytoplasmic localizationGlioblastoma tumor growthLung cancer cellsTET1 expressionFunctional roleSuppressorFactor receptorMember 1TET1SilencingLung cancer samples
2014
Acquired Resistance of EGFR-Mutant Lung Adenocarcinomas to Afatinib plus Cetuximab Is Associated with Activation of mTORC1
Pirazzoli V, Nebhan C, Song X, Wurtz A, Walther Z, Cai G, Zhao Z, Jia P, de Stanchina E, Shapiro EM, Gale M, Yin R, Horn L, Carbone DP, Stephens PJ, Miller V, Gettinger S, Pao W, Politi K. Acquired Resistance of EGFR-Mutant Lung Adenocarcinomas to Afatinib plus Cetuximab Is Associated with Activation of mTORC1. Cell Reports 2014, 7: 999-1008. PMID: 24813888, PMCID: PMC4074596, DOI: 10.1016/j.celrep.2014.04.014.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinomaAdenocarcinoma of LungAfatinibAnimalsAntibodies, Monoclonal, HumanizedAntineoplastic Combined Chemotherapy ProtocolsCell Line, TumorCetuximabDrug Resistance, NeoplasmErbB ReceptorsHumansLung NeoplasmsMechanistic Target of Rapamycin Complex 1MiceMice, NudeMice, TransgenicMultiprotein ComplexesMutationQuinazolinesRandom AllocationTOR Serine-Threonine KinasesXenograft Model Antitumor AssaysConceptsTyrosine kinase inhibitorsFirst-generation tyrosine kinase inhibitorEGFR-mutant lung adenocarcinomaLung adenocarcinomaMechanisms of resistanceEGFR antibody cetuximabPotential therapeutic strategyBiopsy specimensAntibody cetuximabDrug combinationsMouse modelTherapeutic strategiesAfatinibAddition of rapamycinCetuximabDual inhibitionAcquired ResistanceKinase inhibitorsGenomic alterationsAdenocarcinomaPatientsActivationGenomic mechanismsDrugsMTORC1 activationReduced NF1 Expression Confers Resistance to EGFR Inhibition in Lung Cancer
de Bruin EC, Cowell C, Warne PH, Jiang M, Saunders RE, Melnick MA, Gettinger S, Walther Z, Wurtz A, Heynen GJ, Heideman DA, Gómez-Román J, García-Castaño A, Gong Y, Ladanyi M, Varmus H, Bernards R, Smit EF, Politi K, Downward J. Reduced NF1 Expression Confers Resistance to EGFR Inhibition in Lung Cancer. Cancer Discovery 2014, 4: 606-619. PMID: 24535670, PMCID: PMC4011693, DOI: 10.1158/2159-8290.cd-13-0741.Peer-Reviewed Original ResearchConceptsLung cancerMAP-ERK kinase (MEK) inhibitorsEGF receptorEGFR-mutant lung adenocarcinomaKinase inhibitorsHuman lung cancer cell linesResistance of lungSubgroup of patientsLung cancer cell linesCancer cell linesClinical responsivenessCombination therapyEGFR-TKIEGFR mutationsErlotinib resistanceLung adenocarcinomaRAS-ERK signalingEGFR inhibitionMEK inhibitorsErlotinibReduced expressionNF1 expressionPatientsCell linesNeurofibromin levels
2013
Programmed death ligand-1 expression in non-small cell lung cancer
Velcheti V, Schalper KA, Carvajal DE, Anagnostou VK, Syrigos KN, Sznol M, Herbst RS, Gettinger SN, Chen L, Rimm DL. Programmed death ligand-1 expression in non-small cell lung cancer. Laboratory Investigation 2013, 94: 107-116. PMID: 24217091, PMCID: PMC6125250, DOI: 10.1038/labinvest.2013.130.Peer-Reviewed Original ResearchMeSH KeywordsAgedB7-H1 AntigenBiomarkers, TumorCarcinoma, Non-Small-Cell LungCell Line, TumorChi-Square DistributionCohort StudiesConnecticutFemaleGreeceHumansImmunohistochemistryLung NeoplasmsLymphocytes, Tumor-InfiltratingMalePrognosisReproducibility of ResultsRNA, MessengerSurvival AnalysisTissue Array AnalysisConceptsNon-small cell lung cancerPD-L1 expressionCell lung cancerPD-L1Tissue microarrayBetter outcomesNSCLC casesLung cancerDeath ligand 1 (PD-L1) expressionCell death ligand 1PD-L1 protein expressionEarly phase clinical trialsLigand 1 expressionTumor-infiltrating lymphocytesDeath ligand 1Significant better outcomePD-L1 mRNAPD-L1 proteinPhase clinical trialsNormal human placentaPrediction of responseQuantitative fluorescence approachesFrequency of expressionPD-1Prognostic valueHigh SOX2 Levels Predict Better Outcome in Non-Small Cell Lung Carcinomas
Velcheti V, Schalper K, Yao X, Cheng H, Kocoglu M, Dhodapkar K, Deng Y, Gettinger S, Rimm DL. High SOX2 Levels Predict Better Outcome in Non-Small Cell Lung Carcinomas. PLOS ONE 2013, 8: e61427. PMID: 23620753, PMCID: PMC3631238, DOI: 10.1371/journal.pone.0061427.Peer-Reviewed Original ResearchConceptsSquamous cell carcinomaLonger survivalTissue microarrayMultivariate analysisIndependent lung cancer cohortsIndependent positive prognostic markerSOX2 levelsNon-small cell lung carcinomaQuantitative immunofluorescenceLung squamous cell carcinomaSecond independent validation cohortSOX2 expressionHigh SOX2 levelsLog rank pSOX2 overexpressionPositive prognostic markerRisk of deathClinico-pathological characteristicsClinico-pathological variablesCox univariate analysisIndependent validation cohortCell lung carcinomaLung cancer cohortNSCLC patientsOverall survival
2012
Ultrasensitive Measurement of Hotspot Mutations in Tumor DNA in Blood Using Error-Suppressed Multiplexed Deep Sequencing
Narayan A, Carriero NJ, Gettinger SN, Kluytenaar J, Kozak KR, Yock TI, Muscato NE, Ugarelli P, Decker RH, Patel AA. Ultrasensitive Measurement of Hotspot Mutations in Tumor DNA in Blood Using Error-Suppressed Multiplexed Deep Sequencing. Cancer Research 2012, 72: 3492-3498. PMID: 22581825, PMCID: PMC3426449, DOI: 10.1158/0008-5472.can-11-4037.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerTumor DNATumor DNA levelsCell lung cancerCell-free tumor DNATreatment-associated changesDNA levelsTumor-specific mutationsPractical diagnostic testLung cancerPractical clinical implementationPatient samplesDiagnostic testsHotspot mutationsClinical implementationNext-generation sequencingBloodCancer biomarkersSuccessful useNormal DNAMutationsPatientsDeep sequencing
2009
High Expression of Mammalian Target of Rapamycin Is Associated with Better Outcome for Patients with Early Stage Lung Adenocarcinoma
Anagnostou VK, Bepler G, Syrigos KN, Tanoue L, Gettinger S, Homer RJ, Boffa D, Detterbeck F, Rimm DL. High Expression of Mammalian Target of Rapamycin Is Associated with Better Outcome for Patients with Early Stage Lung Adenocarcinoma. Clinical Cancer Research 2009, 15: 4157-4164. PMID: 19509151, DOI: 10.1158/1078-0432.ccr-09-0099.Peer-Reviewed Original ResearchConceptsLung cancer patientsMTOR expressionCancer patientsMammalian targetEarly-stage lung adenocarcinomaHigh mTOR expressionIndependent lower riskMedian overall survivalStage IA patientsProtein expressionSubgroup of patientsLung adenocarcinoma patientsStage lung adenocarcinomaMTOR protein expressionRole of mTOROverall survivalPathologic characteristicsPatient survivalValidation cohortAdenocarcinoma groupAdenocarcinoma patientsPrognostic stratificationLung cancerTraining cohortFavorable outcome