2024
Positive selection CRISPR screens reveal a druggable pocket in an oligosaccharyltransferase required for inflammatory signaling to NF-κB
Lampson B, Ramίrez A, Baro M, He L, Hegde M, Koduri V, Pfaff J, Hanna R, Kowal J, Shirole N, He Y, Doench J, Contessa J, Locher K, Kaelin W. Positive selection CRISPR screens reveal a druggable pocket in an oligosaccharyltransferase required for inflammatory signaling to NF-κB. Cell 2024, 187: 2209-2223.e16. PMID: 38670073, PMCID: PMC11149550, DOI: 10.1016/j.cell.2024.03.022.Peer-Reviewed Original ResearchConceptsWhole-genome CRISPR-Cas9 screenCRISPR-Cas9 screensCryoelectron microscopy studiesCell surface localizationLipopolysaccharide receptor Toll-like receptor 4OST complexToll-like receptor 4CRISPR screensNF-kBCatalytic subunitN-glycosylationActivate NF-kBBase editorsUncompetitive inhibition mechanismNGI-1Molecular mechanismsCatalytic siteLPS-treated cellsOligosaccharyltransferaseDruggable pocketSTT3AReceptor Toll-like receptor 4Drug mechanism of actionStructural studiesInflammatory signaling
2023
ER chaperones use a protein folding and quality control glyco-code
Guay K, Ke H, Canniff N, George G, Eyles S, Mariappan M, Contessa J, Gershenson A, Gierasch L, Hebert D. ER chaperones use a protein folding and quality control glyco-code. Molecular Cell 2023, 83: 4524-4537.e5. PMID: 38052210, PMCID: PMC10790639, DOI: 10.1016/j.molcel.2023.11.006.Peer-Reviewed Original Research
2021
Hypoxia-Guided Therapy for Human Papillomavirus-Associated Oropharynx Cancer
Burtness B, Contessa J. Hypoxia-Guided Therapy for Human Papillomavirus-Associated Oropharynx Cancer. Journal Of The National Cancer Institute 2021, 113: 652-653. PMID: 33429429, PMCID: PMC8168139, DOI: 10.1093/jnci/djaa187.Peer-Reviewed Original Research
2019
Neuregulin Signaling Is a Mechanism of Therapeutic Resistance in Head and Neck Squamous Cell Carcinoma
Baro M, Lopez Sambrooks C, Burtness BA, Lemmon MA, Contessa JN. Neuregulin Signaling Is a Mechanism of Therapeutic Resistance in Head and Neck Squamous Cell Carcinoma. Molecular Cancer Therapeutics 2019, 18: 2124-2134. PMID: 31387891, PMCID: PMC6825559, DOI: 10.1158/1535-7163.mct-19-0163.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, MonoclonalCell Line, TumorCell ProliferationCell SurvivalCetuximabDrug Resistance, NeoplasmFemaleHead and Neck NeoplasmsHumansMiceNeuregulinsProto-Oncogene Proteins c-aktReceptor, ErbB-3Signal TransductionSquamous Cell Carcinoma of Head and NeckUp-RegulationXenograft Model Antitumor AssaysConceptsNeck squamous cell carcinomaSquamous cell carcinomaTherapeutic resistanceCell carcinomaResistant cellsConcentrations of cetuximabEFM-19 cellsCetuximab-resistant cellsActionable therapeutic targetsHNSCC cell linesTumor growth experimentsInhibition of EGFRErbB3 antibodyNeuregulin expressionOverall survivalTreatment regimensCetuximab resistanceTherapeutic targetAutocrine loopLocal controlTumor growthRadiotherapyEGFR inhibitionCetuximabNeuregulin SignalingSelective inhibition of N-linked glycosylation impairs receptor tyrosine kinase processing
Klaver E, Zhao P, May M, Flanagan-Steet H, Freeze HH, Gilmore R, Wells L, Contessa J, Steet R. Selective inhibition of N-linked glycosylation impairs receptor tyrosine kinase processing. Disease Models & Mechanisms 2019, 12: dmm039602. PMID: 31101650, PMCID: PMC6602306, DOI: 10.1242/dmm.039602.Peer-Reviewed Original ResearchConceptsNull cellsReceptor processingEndoplasmic reticulum localizationGlycan site occupancyInsulin-like growth factor 1 receptorReceptor tyrosine kinasesGrowth factor 1 receptorFactor 1 receptorCell surface glycoproteinMutant cellsNGI-1Catalytic subunitReceptor kinaseGlycosylation statusReduced abundanceTyrosine kinaseGlycan occupancyTyrosine receptor kinaseSurface localizationInsulin receptorAbnormal glycosylationProteolytic processingFunctional consequencesCell surfaceGlycosylation
2018
Oligosaccharyltransferase Inhibition Overcomes Therapeutic Resistance to EGFR Tyrosine Kinase Inhibitors
Lopez Sambrooks C, Baro M, Quijano A, Narayan A, Cui W, Greninger P, Egan R, Patel A, Benes CH, Saltzman WM, Contessa JN. Oligosaccharyltransferase Inhibition Overcomes Therapeutic Resistance to EGFR Tyrosine Kinase Inhibitors. Cancer Research 2018, 78: canres.0505.2018. PMID: 30026325, PMCID: PMC6125176, DOI: 10.1158/0008-5472.can-18-0505.Peer-Reviewed Original ResearchConceptsMutant NSCLCMutant non-small cell lung cancerNon-small cell lung cancerSignificant tumor growth delayEGFR-TKI treatmentCell lung cancerTyrosine kinase inhibitor resistanceEGFR tyrosine kinase inhibitor resistanceLung cancer cell linesNGI-1Tumor growth delayEffective therapeutic targetCell linesKinase inhibitor resistanceTumor cell viabilityH1975 xenograftsCancer cell linesTKI treatmentComplex transmembrane proteinsEGFR-TKILung cancerTumor responseCell cycle arrestPreclinical modelsTherapeutic strategiesEditing N-Glycan Site Occupancy with Small-Molecule Oligosaccharyltransferase Inhibitors
Rinis N, Golden JE, Marceau CD, Carette JE, Van Zandt MC, Gilmore R, Contessa JN. Editing N-Glycan Site Occupancy with Small-Molecule Oligosaccharyltransferase Inhibitors. Cell Chemical Biology 2018, 25: 1231-1241.e4. PMID: 30078634, PMCID: PMC6337728, DOI: 10.1016/j.chembiol.2018.07.005.Peer-Reviewed Original ResearchConceptsNGI-1Cellular unfolded protein responseMultisubunit enzyme complexN-glycan site occupancyUnfolded protein responseSubset of glycoproteinsSubunit-specific inhibitorsSecretory pathwayCatalytic subunitProtein responseEnzyme complexTarget proteinsOligosaccharyltransferasePharmacologic inhibitionGlycosylationProteinCell modelBiological effectsInhibitorsStructure-activity relationshipsSTT3BSTT3APharmacological approachesSubunitsSite occupancyCombining precision radiotherapy with molecular targeting and immunomodulatory agents: a guideline by the American Society for Radiation Oncology
Bristow RG, Alexander B, Baumann M, Bratman SV, Brown JM, Camphausen K, Choyke P, Citrin D, Contessa JN, Dicker A, Kirsch DG, Krause M, Le QT, Milosevic M, Morris ZS, Sarkaria JN, Sondel PM, Tran PT, Wilson GD, Willers H, Wong RKS, Harari PM. Combining precision radiotherapy with molecular targeting and immunomodulatory agents: a guideline by the American Society for Radiation Oncology. The Lancet Oncology 2018, 19: e240-e251. PMID: 29726389, DOI: 10.1016/s1470-2045(18)30096-2.Peer-Reviewed Original ResearchConceptsMolecular targetingLocal tumor controlRadiation oncologyRadiation Oncology guidelinesSelection of therapyExternal beam radiotherapyRadiosensitivity of tumorsCancer survival outcomesPrecision radiotherapyAmerican SocietyRadiation dose prescriptionImmunotherapy agentsAberrant cell signalingImmunomodulatory agentsSurvival outcomesOncology guidelinesTumor controlImage-guided external beam radiotherapyPrecision cancer medicineBeam radiotherapyDose prescriptionSolid tumorsRadiotherapyTumor microenvironmentGenetic susceptibility
2017
A Small-Molecule Oligosaccharyltransferase Inhibitor with Pan-flaviviral Activity
Puschnik AS, Marceau CD, Ooi YS, Majzoub K, Rinis N, Contessa JN, Carette JE. A Small-Molecule Oligosaccharyltransferase Inhibitor with Pan-flaviviral Activity. Cell Reports 2017, 21: 3032-3039. PMID: 29241533, PMCID: PMC5734657, DOI: 10.1016/j.celrep.2017.11.054.Peer-Reviewed Original ResearchMeSH KeywordsAntiviral AgentsBenzamidesDengue VirusGene ExpressionGene Expression RegulationGenes, ReporterHEK293 CellsHexosyltransferasesHost-Pathogen InteractionsHumansLuciferasesMembrane ProteinsMicrobial Sensitivity TestsSignal TransductionSulfonamidesVirus ReplicationWest Nile virusYellow fever virusZika VirusConceptsAntiviral activityMosquito-borne flavivirusPromising antiviral activityYellow fever virusNGI-1Strong antiviral activityFlavivirus infectionImportant human pathogenAntiviral compoundsHost factorsViral RNA replicationWest NileFever virusDisease-relevant cell typesGlobal healthInfectionFlavivirusesViral mutantsBroad activityCell typesGenetic determinantsHuman pathogensRNA replicationRecent genetic screenTarget activityEstimating Survival in Patients With Lung Cancer and Brain Metastases: An Update of the Graded Prognostic Assessment for Lung Cancer Using Molecular Markers (Lung-molGPA)
Sperduto PW, Yang TJ, Beal K, Pan H, Brown PD, Bangdiwala A, Shanley R, Yeh N, Gaspar LE, Braunstein S, Sneed P, Boyle J, Kirkpatrick JP, Mak KS, Shih HA, Engelman A, Roberge D, Arvold ND, Alexander B, Awad MM, Contessa J, Chiang V, Hardie J, Ma D, Lou E, Sperduto W, Mehta MP. Estimating Survival in Patients With Lung Cancer and Brain Metastases: An Update of the Graded Prognostic Assessment for Lung Cancer Using Molecular Markers (Lung-molGPA). JAMA Oncology 2017, 3: 827-831. PMID: 27892978, PMCID: PMC5824323, DOI: 10.1001/jamaoncol.2016.3834.Peer-Reviewed Original ResearchConceptsDiagnosis-Specific Graded Prognostic AssessmentBrain metastasesGraded Prognostic AssessmentFuture clinical trialsLung cancerLung-molGPAMedian survivalPrognostic factorsHazard ratioClinical trialsMAIN OUTCOMEPrognostic assessmentLung-molGPA scoreOverall median survivalKarnofsky performance statusMultiple Cox regressionSignificant prognostic factorsCell lung cancerRetrospective database analysisCancer-related mortalityLog-rank testHeterogeneous patient populationClinical decision makingExtracranial metastasesOverall survivalManagement of Brain Metastases in Tyrosine Kinase Inhibitor–Naïve Epidermal Growth Factor Receptor–Mutant Non–Small-Cell Lung Cancer: A Retrospective Multi-Institutional Analysis
Magnuson WJ, Lester-Coll NH, Wu AJ, Yang TJ, Lockney NA, Gerber NK, Beal K, Amini A, Patil T, Kavanagh BD, Camidge DR, Braunstein SE, Boreta LC, Balasubramanian SK, Ahluwalia MS, Rana NG, Attia A, Gettinger SN, Contessa JN, Yu JB, Chiang VL. Management of Brain Metastases in Tyrosine Kinase Inhibitor–Naïve Epidermal Growth Factor Receptor–Mutant Non–Small-Cell Lung Cancer: A Retrospective Multi-Institutional Analysis. Journal Of Clinical Oncology 2017, 35: jco.2016.69.714. PMID: 28113019, DOI: 10.1200/jco.2016.69.7144.Peer-Reviewed Original ResearchMeSH KeywordsAgedAntineoplastic AgentsBrain NeoplasmsCarcinoma, Non-Small-Cell LungCombined Modality TherapyCranial IrradiationDisease-Free SurvivalErbB ReceptorsErlotinib HydrochlorideFemaleHumansLung NeoplasmsMaleMiddle AgedProtein Kinase InhibitorsRadiosurgeryRetrospective StudiesSalvage TherapySurvival RateConceptsWhole brain radiotherapyMulti-institutional analysisEGFR-mutant NSCLCBrain metastasesEGFR-TKIStereotactic radiosurgeryTyrosine kinase inhibitorsOverall survivalEpidermal growth factor receptorGrowth factor receptorIntracranial progressionLung cancerMutant non-small cell lung cancerEGFR-TKI resistance mutationNon-small cell lung cancerIntracranial progression-free survivalRetrospective multi-institutional analysisDeferral of radiotherapyEGFR-TKI useSimilar prognostic featuresUpfront EGFR-TKIProgression-free survivalFactor receptorInferior overall survivalCell lung cancer
2016
Oligosaccharyltransferase inhibition induces senescence in RTK-driven tumor cells
Lopez-Sambrooks C, Shrimal S, Khodier C, Flaherty DP, Rinis N, Charest JC, Gao N, Zhao P, Wells L, Lewis TA, Lehrman MA, Gilmore R, Golden JE, Contessa JN. Oligosaccharyltransferase inhibition induces senescence in RTK-driven tumor cells. Nature Chemical Biology 2016, 12: 1023-1030. PMID: 27694802, PMCID: PMC5393272, DOI: 10.1038/nchembio.2194.Peer-Reviewed Original ResearchMeSH KeywordsBenzamidesCell Cycle CheckpointsCell Line, TumorCell ProliferationCellular SenescenceDose-Response Relationship, DrugEnzyme InhibitorsHexosyltransferasesHigh-Throughput Screening AssaysHumansMembrane ProteinsMolecular StructureReceptor Protein-Tyrosine KinasesStructure-Activity RelationshipSulfonamidesThe Effect of Gene Alterations and Tyrosine Kinase Inhibition on Survival and Cause of Death in Patients With Adenocarcinoma of the Lung and Brain Metastases
Sperduto PW, Yang TJ, Beal K, Pan H, Brown PD, Bangdiwala A, Shanley R, Yeh N, Gaspar LE, Braunstein S, Sneed P, Boyle J, Kirkpatrick JP, Mak KS, Shih HA, Engelman A, Roberge D, Arvold ND, Alexander B, Awad MM, Contessa J, Chiang V, Hardie J, Ma D, Lou E, Sperduto W, Mehta MP. The Effect of Gene Alterations and Tyrosine Kinase Inhibition on Survival and Cause of Death in Patients With Adenocarcinoma of the Lung and Brain Metastases. International Journal Of Radiation Oncology • Biology • Physics 2016, 96: 406-413. PMID: 27598807, PMCID: PMC5575932, DOI: 10.1016/j.ijrobp.2016.06.006.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinomaAgedAged, 80 and overAnaplastic Lymphoma KinaseAntineoplastic AgentsBrain NeoplasmsErbB ReceptorsFemaleGenetic MarkersGenetic Predisposition to DiseaseHumansIncidenceLung NeoplasmsMaleMiddle AgedMutationPolymorphism, Single NucleotidePrevalenceProtein-Tyrosine KinasesReceptor Protein-Tyrosine KinasesRetrospective StudiesRisk FactorsSurvival RateUnited StatesConceptsTyrosine kinase inhibitionBrain metastasesMedian survivalCause of deathGene alterationsDiagnosis of BMMulti-institutional retrospective databaseTKI-naïve patientsRisk of deathLonger median survivalKinase inhibitionALK gene alterationsTreatment patternsCancer mortalityLung cancerPrimary diagnosisRetrospective databaseCommon causeLung adenocarcinomaGroup overallPatientsFirst treatmentPrior trialsEGFRMonths
2015
Extended Survival and Prognostic Factors for Patients With ALK-Rearranged Non–Small-Cell Lung Cancer and Brain Metastasis
Johung KL, Yeh N, Desai NB, Williams TM, Lautenschlaeger T, Arvold ND, Ning MS, Attia A, Lovly CM, Goldberg S, Beal K, Yu JB, Kavanagh BD, Chiang VL, Camidge DR, Contessa JN. Extended Survival and Prognostic Factors for Patients With ALK-Rearranged Non–Small-Cell Lung Cancer and Brain Metastasis. Journal Of Clinical Oncology 2015, 34: 123-129. PMID: 26438117, PMCID: PMC5070549, DOI: 10.1200/jco.2015.62.0138.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAnaplastic Lymphoma KinaseAntineoplastic AgentsBrain NeoplasmsCarbazolesCarcinoma, Non-Small-Cell LungCranial IrradiationCrizotinibDisease-Free SurvivalFemaleFollow-Up StudiesGene RearrangementHumansKaplan-Meier EstimateKarnofsky Performance StatusLung NeoplasmsMaleMiddle AgedMolecular Targeted TherapyNeoplasm StagingPiperidinesPrognosisProtein Kinase InhibitorsProtein-Tyrosine KinasesPyrazolesPyridinesPyrimidinesRadiosurgeryReceptor Protein-Tyrosine KinasesRisk AssessmentRisk FactorsSmokingSulfonesConceptsIntracranial progression-free survivalBrain metastasesProgression-free survivalPrognostic factorsLung cancerMedian intracranial progression-free survivalNon-small cell lung cancerTyrosine kinase inhibitor therapyProgressive brain metastasesRefinement of prognosisKarnofsky performance scorePercent of patientsClinical prognostic factorsPopulation of patientsSingle brain metastasisCell lung cancerKinase inhibitor therapyCox proportional hazardsMulti-institutional studyMedian OSExtracranial metastasesImproved survivalInhibitor therapyInitial treatmentMultivariable analysis
2013
A Clinical Model for Identifying Radiosensitive Tumor Genotypes in Non–Small Cell Lung Cancer
Johung KL, Yao X, Li F, Yu JB, Gettinger SN, Goldberg S, Decker RH, Hess JA, Chiang VL, Contessa JN. A Clinical Model for Identifying Radiosensitive Tumor Genotypes in Non–Small Cell Lung Cancer. Clinical Cancer Research 2013, 19: 5523-5532. PMID: 23897899, DOI: 10.1158/1078-0432.ccr-13-0836.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAnaplastic Lymphoma KinaseAntineoplastic AgentsBrain NeoplasmsCarcinoma, Non-Small-Cell LungErbB ReceptorsFemaleGenotypeHumansLung NeoplasmsMaleMiddle AgedMutationProtein Kinase InhibitorsRadiation ToleranceReceptor Protein-Tyrosine KinasesRecurrenceTranslocation, GeneticTumor BurdenConceptsNon-small cell lung cancerCell lung cancerEML4-ALK translocationGamma knife treatmentLocal controlTumor genotypeLung cancerEGFR mutationsCox proportional hazards modelDistant brain controlDistant brain recurrenceGamma knife radiotherapyEGFR kinase domain mutationsSuperior local controlField local controlKRAS mutation statusProportional hazards modelKinase domain mutationsEGF receptorMetastasis sizeBrain recurrenceBrain metastasesField recurrenceClinical outcomesIndependent predictors