2023
FAK drives resistance to therapy in HPV-negative head and neck cancer in a p53-dependent manner.
Pifer P, Yang L, Kumar M, Xie T, Frederick M, Hefner A, Beadle B, Molkentine D, Molkentine J, Dhawan A, Abdelhakiem M, Osman A, Leibowitz B, Myers J, Pickering C, Sandulache V, Heymach J, Skinner H. FAK drives resistance to therapy in HPV-negative head and neck cancer in a p53-dependent manner. Clinical Cancer Research 2023, 30: 187-197. PMID: 37819945, PMCID: PMC10767302, DOI: 10.1158/1078-0432.ccr-23-0964.Peer-Reviewed Original ResearchConceptsHPV-negative headHPV-negative HNSCC tumorsWorse disease-free survivalNeck squamous cell carcinomaMutant TP53HPV-negative HNSCC cell linesBackbone of therapyDisease-free survivalPlatinum-based chemotherapySquamous cell carcinomaHPV-negative HNSCCHNSCC cell linesCell linesWild-type TP53Cisplatin-resistant cell linesCell carcinomaHNSCC cohortNeck cancerHNSCC tumorsVivo shRNA screenWorse outcomes
2022
High enhancer activity is an epigenetic feature of HPV negative atypical head and neck squamous cell carcinoma
Callahan SC, Kochat V, Liu Z, Raman AT, Divenko M, Schulz J, Terranova CJ, Ghosh AK, Tang M, Johnson FM, Wang J, Skinner HD, Pickering CR, Myers JN, Rai K. High enhancer activity is an epigenetic feature of HPV negative atypical head and neck squamous cell carcinoma. Frontiers In Cell And Developmental Biology 2022, 10: 936168. PMID: 35927986, PMCID: PMC9343809, DOI: 10.3389/fcell.2022.936168.Peer-Reviewed Original ResearchNeck squamous cell carcinomaSquamous cell carcinomaCell carcinomaCell linesHNSCC cell linesAtypical headResistance pathwaysHNSCC subtypesFrequent recurrenceMolecular subtypesHeterogeneous diseaseLipid metabolismSubtypesSignificant mortalityCarcinomaMAPK signalingFuture targetsHigh enhancer activityDiseaseAtypicalsBromodomain inhibitorsTCGA tumorsEnhancer activityBasalMesenchymal
2021
Low doses of methylnaltrexone inhibits head and neck squamous cell carcinoma growth in vitro and in vivo by acting on the mu‐opioid receptor
Gorur A, Patiño M, Shi T, Corrales G, Takahashi H, Rangel R, Gleber‐Netto F, Pickering C, Myers JN, Cata JP. Low doses of methylnaltrexone inhibits head and neck squamous cell carcinoma growth in vitro and in vivo by acting on the mu‐opioid receptor. Journal Of Cellular Physiology 2021, 236: 7698-7710. PMID: 34038587, DOI: 10.1002/jcp.30421.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsCell Line, TumorCell MovementCell ProliferationEpithelial-Mesenchymal TransitionHead and Neck NeoplasmsHumansMaleMice, Inbred C57BLMice, NudeNaltrexoneNarcotic AntagonistsNeoplasm InvasivenessQuaternary Ammonium CompoundsReceptors, Opioid, muSignal TransductionSquamous Cell Carcinoma of Head and NeckTumor BurdenXenograft Model Antitumor AssaysConceptsMu-opioid receptorsEffects of methylnaltrexoneHNSCC cell linesTumor growthCell linesNeck squamous cell carcinoma growthNeck squamous cell carcinomaDifferent HNSCC cell linesClonogenic activitySquamous cell carcinoma growthSquamous cell carcinomaLung cancer cell linesCyclic adenosine monophosphate levelsTumor-bearing miceAggressive cell behaviorEpithelial-mesenchymal transitionAdenosine monophosphate levelsCancer cell linesCell carcinomaMethylnaltrexoneCarcinoma growthTherapeutic targetLow dosesFaDu cellsMetastasis formation
2020
Caspase 8 loss radiosensitizes head and neck squamous cell carcinoma to SMAC mimetic induced necroptosis
Uzunparmak B, Gao M, Lindemann A, Erikson K, Wang L, Lin E, Frank SJ, Gleber-Netto FO, Zhao M, Skinner HD, Newton JM, Sikora AG, Myers JN, Pickering CR. Caspase 8 loss radiosensitizes head and neck squamous cell carcinoma to SMAC mimetic induced necroptosis. JCI Insight 2020, 5: e139837. PMID: 33108350, PMCID: PMC7714407, DOI: 10.1172/jci.insight.139837.Peer-Reviewed Original ResearchConceptsReceptor-interacting serine/threonine-protein kinase 3Caspase-8Serine/threonine-protein kinase 3Regulated cell death mechanismsPan-caspase inhibitor z-VADSecond mitochondria-derived activatorProtein kinase 3Cell death mechanismsRIP3 functionSmac mimeticsZ-VADKinase 3Death mechanismsMolecular underpinningsNecroptosis pathwayHNSCC cell linesNecroptosisRIP3 expressionCancer cellsCell linesBirinapantNeck squamous cell carcinomaCASP8 mutationsSquamous cell carcinomaSyngeneic mouse modelTargeting DNA damage response in head and neck cancers through abrogation of cell cycle checkpoints
Molkentine JM, Molkentine DP, Bridges KA, Xie T, Yang L, Sheth A, Heffernan TP, Clump DA, Faust AZ, Ferris RL, Myers JN, Frederick MJ, Mason KA, Meyn RE, Pickering CR, Skinner HD. Targeting DNA damage response in head and neck cancers through abrogation of cell cycle checkpoints. International Journal Of Radiation Biology 2020, 97: 1121-1128. PMID: 32073931, PMCID: PMC7483862, DOI: 10.1080/09553002.2020.1730014.Peer-Reviewed Original ResearchConceptsHPV statusHPV(-) cellsNeck cancerPARP inhibitionPCR arrayDNA repair genesSignificant radiosensitizationBeneficial treatment optionPARP inhibitor niraparibEffective treatment strategiesHNSCC cell linesNormal tissue toxicityRepair genesShRNA screenRole of p16HPV- tumorsHNSCC xenograftsTreatment optionsTreatment modalitiesTreatment strategiesTherapeutic ratioLimited progressionHPVP16 expressionNiraparib
2019
PDK1 Mediates NOTCH1-Mutated Head and Neck Squamous Carcinoma Vulnerability to Therapeutic PI3K/mTOR Inhibition
Sambandam V, Frederick MJ, Shen L, Tong P, Rao X, Peng S, Singh R, Mazumdar T, Huang C, Li Q, Pickering CR, Myers JN, Wang J, Johnson FM. PDK1 Mediates NOTCH1-Mutated Head and Neck Squamous Carcinoma Vulnerability to Therapeutic PI3K/mTOR Inhibition. Clinical Cancer Research 2019, 25: 3329-3340. PMID: 30770351, PMCID: PMC6548600, DOI: 10.1158/1078-0432.ccr-18-3276.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisCell Line, TumorCell ProliferationCRISPR-Cas SystemsDisease Models, AnimalDose-Response Relationship, DrugGene EditingGene ExpressionGene Knockdown TechniquesHumansLoss of Function MutationMicePhosphatidylinositol 3-KinasesProtein Kinase InhibitorsPyruvate Dehydrogenase Acetyl-Transferring KinaseReceptor, Notch1Signal TransductionSquamous Cell Carcinoma of Head and NeckTOR Serine-Threonine KinasesConceptsPI3K/mTOR inhibitorPI3K/mTOR inhibitionPI3K/mTOR pathway inhibitorsMTOR pathway inhibitorsHNSCC cell linesMTOR inhibitorsMTOR inhibitionCell linesPathway inhibitorNeck squamous cell carcinomaDrug-sensitive cell linesClinical response ratePI3K/mTOR pathwaySquamous cell carcinomaBiomarkers of responseOrthotopic xenograft modelCell carcinomaTumor sizeXenograft modelHNSCCSingle agentPDK1 overexpressionResponse rateMolecular vulnerabilitiesPharmacogenomic approachDisruption of TP63-miR-27a* Feedback Loop by Mutant TP53 in Head and Neck Cancer
Chari NS, Ivan C, Le X, Li J, Mijiti A, Patel AA, Osman AA, Peterson CB, Williams MD, Pickering CR, Caulin C, Myers JN, Calin GA, Lai SY. Disruption of TP63-miR-27a* Feedback Loop by Mutant TP53 in Head and Neck Cancer. Journal Of The National Cancer Institute 2019, 112: 266-277. PMID: 31124563, PMCID: PMC7073912, DOI: 10.1093/jnci/djz097.Peer-Reviewed Original ResearchMeSH KeywordsCase-Control StudiesChromatin ImmunoprecipitationFeedback, PhysiologicalHead and Neck NeoplasmsHumansMicroRNAsMouth NeoplasmsMutationNeoplasm StagingPromoter Regions, GeneticSquamous Cell Carcinoma of Head and NeckSurvival RateTranscription FactorsTranscription, GeneticTumor Suppressor Protein p53Tumor Suppressor ProteinsConceptsMutant TP53Neck squamous cell carcinomaSquamous cell carcinomaHNSCC cell linesInhibits tumor growthEpidermal growth factor receptorFrequent eventRole of TP53PI3K pathwayGrowth factor receptorCancer Genome AtlasCell carcinomaNeck cancerHNSCC samplesPoor survivalEpidermal growth factorTumor growthVivo findingsTumor progressionPatient samplesTumor samplesTumor survivalTumor cellsNormal tissuesNovel target
2017
Replication Stress Leading to Apoptosis within the S-phase Contributes to Synergism between Vorinostat and AZD1775 in HNSCC Harboring High-Risk TP53 Mutation
Tanaka N, Patel AA, Tang L, Silver NL, Lindemann A, Takahashi H, Jaksik R, Rao X, Kalu NN, Chen TC, Wang J, Frederick MJ, Johnson F, Gleber-Netto FO, Fu S, Kimmel M, Wang J, Hittelman WN, Pickering CR, Myers JN, Osman AA. Replication Stress Leading to Apoptosis within the S-phase Contributes to Synergism between Vorinostat and AZD1775 in HNSCC Harboring High-Risk TP53 Mutation. Clinical Cancer Research 2017, 23: 6541-6554. PMID: 28790110, PMCID: PMC5724758, DOI: 10.1158/1078-0432.ccr-17-0947.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisCarcinoma, Squamous CellCell Cycle ProteinsCell Line, TumorCell ProliferationDNA DamageDNA ReplicationDrug SynergismFemaleHead and Neck NeoplasmsHistone Deacetylase InhibitorsHumansHydroxamic AcidsMiceMutationNuclear ProteinsPhosphorylationProtein-Tyrosine KinasesPyrazolesPyrimidinesPyrimidinonesRisk FactorsS PhaseSquamous Cell Carcinoma of Head and NeckTumor Suppressor Protein p53VorinostatConceptsOrthotopic mouse modelHNSCC cellsOral cancerMouse modelNeck squamous cell carcinomaSquamous cell carcinomaCombination of vorinostatProlongs animal survivalHNSCC cell linesClin Cancer ResClonogenic survival assaysAdvanced HNSCCAdvanced headStandard therapyCell carcinomaCure rateEffective therapyClinical investigationCell cycleP53 mutationsTumor growthVorinostatAnimal survivalAZD1775Cancer ResIntegrative Analysis Identifies a Novel AXL–PI3 Kinase–PD-L1 Signaling Axis Associated with Radiation Resistance in Head and Neck Cancer
Skinner HD, Giri U, Yang LP, Kumar M, Liu Y, Story MD, Pickering CR, Byers LA, Williams MD, Wang J, Shen L, Yoo SY, Fan YH, Molkentine DP, Beadle BM, Meyn RE, Myers JN, Heymach JV. Integrative Analysis Identifies a Novel AXL–PI3 Kinase–PD-L1 Signaling Axis Associated with Radiation Resistance in Head and Neck Cancer. Clinical Cancer Research 2017, 23: 2713-2722. PMID: 28476872, PMCID: PMC5457365, DOI: 10.1158/1078-0432.ccr-16-2586.Peer-Reviewed Original ResearchMeSH KeywordsAgedAxl Receptor Tyrosine KinaseB7-H1 AntigenBiomarkers, TumorCarcinoma, Squamous CellCell Line, TumorFemaleGene Expression Regulation, NeoplasticHead and Neck NeoplasmsHumansLymphocytes, Tumor-InfiltratingMaleMiddle AgedPapillomaviridaePhosphatidylinositol 3-KinasesProteomicsProto-Oncogene ProteinsRadiation ToleranceReceptor Protein-Tyrosine KinasesRNA, MessengerSignal TransductionConceptsPD-L1HPV-negative HNSCC tumorsNeck squamous cell carcinomaCell linesHPV-negative HNSCC cell linesLocal failureLocal treatment failurePD-L1 axisPD-L1 expressionTumor-infiltrating lymphocytesSquamous cell carcinomaHuman papilloma virusLow expression groupActivation of AxlHNSCC cell linesClin Cancer ResNegative cell linesTreatment failureCell carcinomaPapilloma virusHNSCC tumorsExpression groupMultivariate analysisMRNA expression analysisPI3-kinaseMutations of the LIM protein AJUBA mediate sensitivity of head and neck squamous cell carcinoma to treatment with cell-cycle inhibitors
Zhang M, Singh R, Peng S, Mazumdar T, Sambandam V, Shen L, Tong P, Li L, Kalu NN, Pickering CR, Frederick M, Myers JN, Wang J, Johnson FM. Mutations of the LIM protein AJUBA mediate sensitivity of head and neck squamous cell carcinoma to treatment with cell-cycle inhibitors. Cancer Letters 2017, 392: 71-82. PMID: 28126323, PMCID: PMC5404895, DOI: 10.1016/j.canlet.2017.01.024.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsApoptosisCarcinoma, Squamous CellCell Cycle ProteinsCell Line, TumorCell ProliferationCheckpoint Kinase 1Checkpoint Kinase 2Dose-Response Relationship, DrugG2 Phase Cell Cycle CheckpointsGenotypeHead and Neck NeoplasmsHumansLIM Domain ProteinsMice, NudeMolecular Targeted TherapyMutationNuclear ProteinsPhenotypeProtein Kinase InhibitorsProtein Serine-Threonine KinasesProtein-Tyrosine KinasesProto-Oncogene ProteinsPteridinesPyrazolesPyrimidinesPyrimidinonesRas ProteinsRNA InterferenceSignal TransductionSmad4 ProteinSquamous Cell Carcinoma of Head and NeckThiophenesTime FactorsTransfectionTumor BurdenUreaXenograft Model Antitumor AssaysConceptsPolo-like kinase 1Cell linesLIM protein AjubaHNSCC cell linesInhibitor-induced apoptosisProtein expressionCell cycle inhibitorsCell cycle arrestKnockdown of PLK1Neck squamous cell carcinomaAjubaExogenous expressionNeck squamous cell carcinoma (HNSCC) tumorsSquamous cell carcinoma tumorsKinase 1HNSCC mouse modelSquamous cell carcinomaSubstrate inhibitionHigher drug dosesPotential candidate biomarkersGenomic alterationsMitotic inhibitorsPLK1 inhibitionSensitive cell linesMutations
2016
Proteomic Profiling Identifies PTK2/FAK as a Driver of Radioresistance in HPV-negative Head and Neck Cancer
Skinner HD, Giri U, Yang L, Woo SH, Story MD, Pickering CR, Byers LA, Williams MD, El-Naggar A, Wang J, Diao L, Shen L, Fan YH, Molkentine DP, Beadle BM, Meyn RE, Myers JN, Heymach JV. Proteomic Profiling Identifies PTK2/FAK as a Driver of Radioresistance in HPV-negative Head and Neck Cancer. Clinical Cancer Research 2016, 22: 4643-4650. PMID: 27036135, PMCID: PMC5061056, DOI: 10.1158/1078-0432.ccr-15-2785.Peer-Reviewed Original ResearchConceptsHPV-negative HNSCC cell linesHPV-negative HNSCCHNSCC cell linesTargetable biomarkersHuman papillomavirusIndependent cohortCandidate biomarkersPoor disease-free survivalNeck squamous cell carcinomaBiomarker of radioresistanceDisease-free survivalSquamous cell carcinomaDisease-related mortalityMerit further evaluationCell linesFAK inhibitionG2-M arrestFocal adhesion kinaseAdvanced HNSCCWorse DFSCancer Genome AtlasCell carcinomaPharmacologic blockadeCancer subgroupsFAK overexpression
2015
Down‐regulation of malic enzyme 1 and 2: Sensitizing head and neck squamous cell carcinoma cells to therapy‐induced senescence
Woo SH, Yang LP, Chuang HC, Fitzgerald A, Lee HY, Pickering C, Myers JN, Skinner HD. Down‐regulation of malic enzyme 1 and 2: Sensitizing head and neck squamous cell carcinoma cells to therapy‐induced senescence. Head & Neck 2015, 38: e934-e940. PMID: 25994759, DOI: 10.1002/hed.24129.Peer-Reviewed Original ResearchMeSH KeywordsCarcinoma, Squamous CellCell Line, TumorCellular SenescenceCyclin-Dependent Kinase Inhibitor p21Down-RegulationGene Expression Regulation, NeoplasticGene Knockdown TechniquesHead and Neck NeoplasmsHumansMalate DehydrogenaseMetforminRadiation, IonizingReactive Oxygen SpeciesTumor Suppressor Protein p53ConceptsTherapy-induced senescenceOverall survivalReactive oxygen speciesNeck squamous cell carcinomaSquamous cell carcinomaPoor overall survivalPotential therapeutic benefitHNSCC cell linesAntioxidant N-acetyl cysteineN-acetyl cysteinePoor outcomeCell carcinomaPatient outcomesHNSCC cellsGeneration of ROSTherapeutic benefitME2 expressionInduction of senescenceHNSCCP53 statusHigh expressionEnzyme expressionCell linesOxygen speciesOutcomes
2014
HRAS mutations and resistance to the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in head and neck squamous cell carcinoma cells
Hah JH, Zhao M, Pickering CR, Frederick MJ, Andrews GA, Jasser SA, Fooshee DR, Milas ZL, Galer C, Sano D, William WN, Kim E, Heymach J, Byers LA, Papadimitrakopoulou V, Myers JN. HRAS mutations and resistance to the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in head and neck squamous cell carcinoma cells. Head & Neck 2014, 36: 1547-1554. PMID: 24123531, PMCID: PMC4010580, DOI: 10.1002/hed.23499.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlotting, WesternCarcinoma, Squamous CellCell Line, TumorCell ProliferationDown-RegulationDrug Resistance, NeoplasmErlotinib HydrochlorideHead and Neck NeoplasmsHumansMiceMolecular Targeted TherapyMutationProtein Kinase InhibitorsProto-Oncogene Proteins p21(ras)QuinazolinesSensitivity and SpecificitySignal TransductionSquamous Cell Carcinoma of Head and NeckTransfectionConceptsShort hairpin RNACell linesHRAS expressionErlotinib sensitivityErlotinib-sensitive cell linesErlotinib-resistant cell linesErlotinib resistanceHRAS mutationsNeck squamous cell carcinoma cellsEpidermal growth factor receptor tyrosine kinase inhibitorsGrowth factor receptor tyrosine kinase inhibitorsEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinibNeck squamous cell carcinoma cell linesSquamous cell carcinoma cellsTyrosine kinase inhibitor erlotinibPanel of headReceptor tyrosine kinase inhibitorsHairpin RNAHNSCC cell linesSquamous cell carcinoma cell linesCell carcinoma cell linesCarcinoma cell linesKinase inhibitor erlotinibTyrosine kinase inhibitorsMutations
2013
Coordinated Targeting of the EGFR Signaling Axis by MicroRNA-27a*
Wu X, Bhayani MK, Dodge CT, Nicoloso MS, Chen Y, Yan X, Adachi M, Thomas L, Galer CE, Jiffar T, Pickering CR, Kupferman ME, Myers JN, Calin GA, Lai SY. Coordinated Targeting of the EGFR Signaling Axis by MicroRNA-27a*. Oncotarget 2013, 4: 1388-1398. PMID: 23963114, PMCID: PMC3824521, DOI: 10.18632/oncotarget.1239.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBinding SitesCarcinoma, Squamous CellCell Growth ProcessesCell Line, TumorCell SurvivalDown-RegulationErbB ReceptorsHead and Neck NeoplasmsHumansMiceMicroRNAsProto-Oncogene Proteins c-aktRNA, MessengerSignal TransductionSquamous Cell Carcinoma of Head and NeckTOR Serine-Threonine KinasesXenograft Model Antitumor AssaysConceptsEpidermal growth factor receptorDownregulation of EGFRSolid tumorsTumor growthNeck squamous cell carcinomaMurine orthotopic xenograft modelHNSCC cell viabilityOral cavity cancerMultiple HNSCC cell linesSquamous cell carcinomaStar strandNovel therapeutic optionsNovel miRNAsMultiple solid tumorsOrthotopic xenograft modelOverexpression of EGFRCoordinated regulationHNSCC cell linesCoordinated targetingGrowth factor receptorComplex regulationDirect intratumoral injectionPathway componentsInducible expressionSignaling Axis
2011
Disruptive TP53 Mutation Is Associated with Aggressive Disease Characteristics in an Orthotopic Murine Model of Oral Tongue Cancer
Sano D, Xie TX, Ow TJ, Zhao M, Pickering CR, Zhou G, Sandulache VC, Wheeler DA, Gibbs RA, Caulin C, Myers JN. Disruptive TP53 Mutation Is Associated with Aggressive Disease Characteristics in an Orthotopic Murine Model of Oral Tongue Cancer. Clinical Cancer Research 2011, 17: 6658-6670. PMID: 21903770, PMCID: PMC3207013, DOI: 10.1158/1078-0432.ccr-11-0046.Peer-Reviewed Original ResearchConceptsDisruptive TP53 mutationsCervical lymph node metastasisOral tongue cancerLymph node metastasisOrthotopic murine modelHNSCC cell linesTP53 mutationsNode metastasisTongue cancerMurine modelCell linesTumor growthNeck squamous cell carcinoma cell linesSquamous cell carcinoma cell linesAggressive disease characteristicsCell carcinoma cell linesFaster tumor growthPoor patient outcomesP53 protein expressionTP53 mutation statusBehavior of tumorsWild-type TP53Western blot analysisOral tongueShorter survivalIndividualizing antimetabolic treatment strategies for head and neck squamous cell carcinoma based on TP53 mutational status
Sandulache VC, Skinner HD, Ow TJ, Zhang A, Xia X, Luchak JM, Wong L, Pickering CR, Zhou G, Myers JN. Individualizing antimetabolic treatment strategies for head and neck squamous cell carcinoma based on TP53 mutational status. Cancer 2011, 118: 711-721. PMID: 21720999, PMCID: PMC3188683, DOI: 10.1002/cncr.26321.Peer-Reviewed Original ResearchConceptsMitochondrial respirationGlycolytic dependenceHNSCC cellsAltered tumor cell metabolismGlycolytic inhibitionTumor suppressor geneTumor cell metabolismTP53 mutational statusMitochondrial reserveInhibition of respirationMetabolic shiftCell metabolismCellular resistanceSuppressor geneHNSCC cell linesMutational statusGlycolytic fluxCell linesRespirationNeck squamous cell carcinomaMutationsGlycolysisCellsClonogenic assayRadioresistance