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 SignalingOligosaccharyltransferase Inhibition Reduces Receptor Tyrosine Kinase Activation and Enhances Glioma Radiosensitivity
Baro M, Sambrooks C, Quijano A, Saltzman WM, Contessa J. Oligosaccharyltransferase Inhibition Reduces Receptor Tyrosine Kinase Activation and Enhances Glioma Radiosensitivity. Clinical Cancer Research 2019, 25: 784-795. PMID: 29967251, PMCID: PMC6314911, DOI: 10.1158/1078-0432.ccr-18-0792.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsCell Cycle CheckpointsCell Line, TumorCell SurvivalDisease Models, AnimalDose-Response Relationship, DrugDose-Response Relationship, RadiationErbB ReceptorsGliomaHexosyltransferasesHumansMembrane ProteinsMiceRadiation ToleranceRadiation-Sensitizing AgentsReceptor Protein-Tyrosine KinasesSignal TransductionXenograft Model Antitumor AssaysConceptsNGI-1Cell cycle arrestDNA damageReceptor tyrosine kinase activationTyrosine kinase activationReceptor tyrosine kinasesSmall molecule inhibitorsEGFR family receptorsRTK signalingRTK activationXenograft tumor growthGlycosylation stateKinase activationTumor cell radiosensitivityExpression profilesProtein NTyrosine kinaseGlioma radiosensitivityParallel signalingTumor growthFamily activationCellular radiosensitivityFamily receptorsMechanistic roleProtein levels