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
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 Signaling
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 activity