2024
Sequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial
Ascierto P, Casula M, Bulgarelli J, Pisano M, Piccinini C, Piccin L, Cossu A, Mandalà M, Ferrucci P, Guidoboni M, Rutkowski P, Ferraresi V, Arance A, Guida M, Maiello E, Gogas H, Richtig E, Fierro M, Lebbe C, Helgadottir H, Queirolo P, Spagnolo F, Tucci M, Del Vecchio M, Cao M, Minisini A, De Placido S, Sanmamed M, Mallardo D, Paone M, Vitale M, Melero I, Grimaldi A, Giannarelli D, Dummer R, Sileni V, Palmieri G. Sequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial. Nature Communications 2024, 15: 146. PMID: 38167503, PMCID: PMC10761671, DOI: 10.1038/s41467-023-44475-6.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic Combined Chemotherapy ProtocolsHumansImmunotherapyIpilimumabMelanomaMitogen-Activated Protein Kinase KinasesMutationProtein Kinase InhibitorsProto-Oncogene Proteins B-rafSkin NeoplasmsConceptsOverall survivalSurvival outcomesNoncomparative phase II trialTotal progression-free survivalLong-term survival outcomesMEK inhibitionBRAF/MEK inhibitionFirst-line treatment approachFirst-line treatment optionBRAF/MEK inhibitorsT-lymphocyte antigen-4Cell death protein 1BRAFV600-mutant melanomaDual checkpoint blockadeFirst-line immunotherapyMetastatic BRAF V600Serum interferon gammaPhase II trialProgression-free survivalDeath protein 1BRAFV600-mutant metastatic melanomaLow baseline levelsBiomarker analysisCombination BRAFSequential immunotherapyCombined BET and MEK Inhibition synergistically suppresses melanoma by targeting YAP1
Hu R, Hou H, Li Y, Zhang M, Li X, Chen Y, Guo Y, Sun H, Zhao S, Liao M, Cao D, Yan Q, Chen X, Yin M. Combined BET and MEK Inhibition synergistically suppresses melanoma by targeting YAP1. Theranostics 2024, 14: 593-607. PMID: 38169595, PMCID: PMC10758063, DOI: 10.7150/thno.85437.Peer-Reviewed Original ResearchMeSH KeywordsBromodomain Containing ProteinsCell Cycle ProteinsCell Line, TumorHumansMelanomaMitogen-Activated Protein Kinase KinasesNuclear ProteinsProtein Kinase InhibitorsProto-Oncogene Proteins B-rafPyridonesTranscription FactorsConceptsMEK inhibitor resistanceMEK inhibitor trametinibTrametinib treatmentInhibitor resistanceInhibitor trametinibMelanoma patientsYAP1 expressionMEK inhibitionBRAF-mutant melanoma patientsResistance to MEK inhibitionYAP1 inhibitionResistance to trametinibMelanoma growth <i>inInhibition of BRD4Trametinib resistanceAntitumor effectMelanoma growthTrametinibNHWD-870YAP1 inhibitorDrug resistanceMelanomaMelanoma samplesMelanoma cellsBRD4 depletion
2023
Combined PD-1, BRAF and MEK inhibition in BRAFV600E colorectal cancer: a phase 2 trial
Tian J, Chen J, Chao S, Pelka K, Giannakis M, Hess J, Burke K, Jorgji V, Sindurakar P, Braverman J, Mehta A, Oka T, Huang M, Lieb D, Spurrell M, Allen J, Abrams T, Clark J, Enzinger A, Enzinger P, Klempner S, McCleary N, Meyerhardt J, Ryan D, Yurgelun M, Kanter K, Van Seventer E, Baiev I, Chi G, Jarnagin J, Bradford W, Wong E, Michel A, Fetter I, Siravegna G, Gemma A, Sharpe A, Demehri S, Leary R, Campbell C, Yilmaz O, Getz G, Parikh A, Hacohen N, Corcoran R. Combined PD-1, BRAF and MEK inhibition in BRAFV600E colorectal cancer: a phase 2 trial. Nature Medicine 2023, 29: 458-466. PMID: 36702949, PMCID: PMC9941044, DOI: 10.1038/s41591-022-02181-8.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic Combined Chemotherapy ProtocolsColorectal NeoplasmsHumansMelanomaMitogen-Activated Protein Kinase KinasesMutationProgrammed Cell Death 1 ReceptorProtein Kinase InhibitorsProto-Oncogene Proteins B-rafPyridonesPyrimidinonesConceptsPrimary end pointColorectal cancerResponse rateEnd pointPD-1Immune responseSingle-arm phase 2 clinical trialMAPK inhibitionMEK inhibitionPhase 2 clinical trialTreatment tumor biopsiesDisease control rateSecondary end pointsPhase 2 trialProgression-free survivalBetter clinical outcomesDuration of responseOverall response rateTumor immune responseFurther clinical evaluationTumor cell-intrinsic mechanismsMAPK pathway inhibitionPatient-derived organoidsCell-intrinsic mechanismsOverall survivalProteome-wide screening for mitogen-activated protein kinase docking motifs and interactors
Shi G, Song C, Torres Robles J, Salichos L, Lou H, Lam T, Gerstein M, Turk B. Proteome-wide screening for mitogen-activated protein kinase docking motifs and interactors. Science Signaling 2023, 16: eabm5518. PMID: 36626580, PMCID: PMC9995140, DOI: 10.1126/scisignal.abm5518.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceHumansMitogen-Activated Protein Kinase KinasesMitogen-Activated Protein Kinasesp38 Mitogen-Activated Protein KinasesPhosphorylationProtein BindingProteomeConceptsMitogen-activated protein kinaseDocking motifSequence motifsDocking sequenceShort linear sequence motifsLinear sequence motifsSubstrate recruitmentHuman proteomeProtein kinaseCatalytic cleftExchange mutantsEssential functionsCultured cellsScreening pipelineWide screeningInteractorsMotifSequenceLimited repertoireSelective bindingInteractomeCombinatorial librariesMKK6ProteomeMKK7
2022
RASGRF1 Fusions Activate Oncogenic RAS Signaling and Confer Sensitivity to MEK Inhibition.
Hunihan L, Zhao D, Lazowski H, Li M, Qian Y, Abriola L, Surovtseva YV, Muthusamy V, Tanoue LT, Rothberg BE, Schalper KA, Herbst RS, Wilson FH. RASGRF1 Fusions Activate Oncogenic RAS Signaling and Confer Sensitivity to MEK Inhibition. Clinical Cancer Research 2022, 28: 3091-3103. PMID: 35247929, PMCID: PMC9288503, DOI: 10.1158/1078-0432.ccr-21-4291.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinoma of LungCarcinogenesisHumansLung NeoplasmsMitogen-Activated Protein Kinase Kinasesras-GRF1ConceptsLung adenocarcinomaSmoking historyPack-year smoking historyMinimal smoking historySubset of patientsPancreatic ductal adenocarcinoma cell linesPotential treatment strategyTight junction protein occludinJunction protein occludinWhole-exome sequencingAdenocarcinoma cell lineAdvanced malignanciesCancer Genome AtlasRaf-MEKAdvanced tumorsMultiple malignanciesTreatment strategiesKRAS mutationsTherapeutic strategiesTherapeutic targetOncogenic RAS SignalingRelated commentaryOncogenic driversMEK inhibitionOncogenic alterationsInhibition of MEK-ERK signaling reduces seizures in two mouse models of tuberous sclerosis complex
Nguyen LH, Leiser SC, Song D, Brunner D, Roberds SL, Wong M, Bordey A. Inhibition of MEK-ERK signaling reduces seizures in two mouse models of tuberous sclerosis complex. Epilepsy Research 2022, 181: 106890. PMID: 35219048, PMCID: PMC8930622, DOI: 10.1016/j.eplepsyres.2022.106890.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDisease Models, AnimalHumansMiceMitogen-Activated Protein Kinase KinasesSeizuresSignal TransductionTuberous SclerosisConceptsTuberous sclerosis complexMouse modelTSC mouse modelsDevelopmental brain malformationsMEK-ERKNovel treatment targetsMEK inhibitor PD0325901Intractable epilepsySeizure activityTSC patientsSeizure suppressionBrain malformationsMTOR inhibitorsTreatment targetsMEK-ERK activitySeizuresTSC neuropathologyPotential alternative strategyMEK-ERK inhibitionInhibitor PD0325901Monogenic disordersInhibitionMTORTreatmentEverolimus
2021
RAF1 amplification drives a subset of bladder tumors and confers sensitivity to MAPK-directed therapeutics
Bekele RT, Samant AS, Nassar AH, So J, Garcia EP, Curran CR, Hwang JH, Mayhew DL, Nag A, Thorner AR, Börcsök J, Sztupinszki Z, Pan CX, Bellmunt J, Kwiatkowski DJ, Sonpavde GP, Van Allen EM, Mouw KW. RAF1 amplification drives a subset of bladder tumors and confers sensitivity to MAPK-directed therapeutics. Journal Of Clinical Investigation 2021, 131 PMID: 34554931, PMCID: PMC8592548, DOI: 10.1172/jci147849.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell Line, TumorFemaleGene AmplificationGTP PhosphohydrolasesHumansMembrane ProteinsMiceMitogen-Activated Protein Kinase KinasesProtein Kinase InhibitorsProto-Oncogene Proteins c-rafProto-Oncogene Proteins p21(ras)Urinary Bladder NeoplasmsConceptsBladder tumorsUrothelial tumorsTherapeutic strategiesNovel therapeutic strategiesRational therapeutic strategiesPatient-derived modelsRaf/MEK/ERKClinical outcomesMEK/ERKTreatment optionsBladder cancerHeterogeneous diseaseMEK inhibitionTumorsUnique subsetFocal amplificationRAF inhibitorsCell linesRAF1Gene expression patternsActivationExpression patternsSignalingSubsetRaf1 activityReprogramming of bivalent chromatin states in NRAS mutant melanoma suggests PRC2 inhibition as a therapeutic strategy
Terranova C, Tang M, Maitituoheti M, Raman A, Ghosh A, Schulz J, Amin S, Orouji E, Tomczak K, Sarkar S, Oba J, Creasy C, Wu C, Khan S, Lazcano R, Wani K, Singh A, Barrodia P, Zhao D, Chen K, Haydu L, Wang W, Lazar A, Woodman S, Bernatchez C, Rai K. Reprogramming of bivalent chromatin states in NRAS mutant melanoma suggests PRC2 inhibition as a therapeutic strategy. Cell Reports 2021, 36: 109410. PMID: 34289358, PMCID: PMC8369408, DOI: 10.1016/j.celrep.2021.109410.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell Line, TumorCell ProliferationChromatinEnhancer of Zeste Homolog 2 ProteinFemaleGTP PhosphohydrolasesHistonesHumansMelanocytesMelanomaMembrane ProteinsMesodermMice, NudeMitogen-Activated Protein Kinase KinasesMutationNeoplasm MetastasisPolycomb Repressive Complex 2Transcription, GeneticTumor BurdenConceptsHistone H3 lysine 27 trimethylationH3 lysine 27 trimethylationBivalent chromatin stateCell identity genesLysine 27 trimethylationKey epigenetic alterationsNRAS mutantsMaster transcription factorBivalent domainsChromatin statePRC2 inhibitionEpigenetic elementsTranscription factorsEpigenetic alterationsGenetic driversMesenchymal phenotypeNRAS-mutant melanomaState profilingTherapeutic vulnerabilitiesInvasive capacityPharmacological inhibitionMutantsTherapeutic strategiesMelanoma samplesMutant melanoma patientsPPP6C negatively regulates oncogenic ERK signaling through dephosphorylation of MEK
Cho E, Lou HJ, Kuruvilla L, Calderwood DA, Turk BE. PPP6C negatively regulates oncogenic ERK signaling through dephosphorylation of MEK. Cell Reports 2021, 34: 108928. PMID: 33789117, PMCID: PMC8068315, DOI: 10.1016/j.celrep.2021.108928.Peer-Reviewed Original ResearchMeSH KeywordsCarcinogenesisCell Line, TumorHEK293 CellsHumansMAP Kinase Signaling SystemMitogen-Activated Protein Kinase KinasesPhosphoprotein PhosphatasesPhosphorylationRNA, Small InterferingSubstrate SpecificityConceptsProtein kinase cascadeCore oncogenic pathwaysKey negative regulatorOncogenic ERKERK pathway activationCrosstalk regulationCentral kinaseKinase cascadePhosphorylation sitesRegulatory subunitRaf-MEKNegative regulatorERK pathwayDrug targetsOncogenic pathwaysMEKMEK inhibitorsDephosphorylationPathway activationPPP6CPhosphatasePathwayERKHyperphosphorylationCascade
2020
In-depth proteome analysis of more than 12,500 proteins in buffalo mammary epithelial cell line identifies protein signatures for active proliferation and lactation
Jaswal S, Anand V, Kumar S, Bathla S, Dang A, Kaushik J, Mohanty A. In-depth proteome analysis of more than 12,500 proteins in buffalo mammary epithelial cell line identifies protein signatures for active proliferation and lactation. Scientific Reports 2020, 10: 4834. PMID: 32179766, PMCID: PMC7075962, DOI: 10.1038/s41598-020-61521-1.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBuffaloesCell LineCell ProliferationEpithelial CellsFemaleHumansInsulinLactationMammary Glands, HumanMitogen-Activated Protein Kinase KinasesPhosphatidylinositol 3-KinasesProteinsProteomeProteomicsReceptors, NotchSignal TransductionConceptsMammary epithelial cellsSub-cellular fractionsDifferentiated mammary epithelial cellsNon-redundant proteinsBuffalo mammary epithelial cellsMammary epithelial cell lineMolecular pathwaysCGMP-PKG signaling pathwayActive proliferationMammary glandMembranous organellesEpithelial cell lineProteomic analysisKEGG analysisSecretion processNotch signalingSignaling pathwayProteomicsNetwork of ductsProteomic profilingCellular activitiesCGMP-PKGProteinProtein signaturesCell lines
2018
Overcoming Resistance to Dual Innate Immune and MEK Inhibition Downstream of KRAS
Kitajima S, Asahina H, Chen T, Guo S, Quiceno L, Cavanaugh J, Merlino A, Tange S, Terai H, Kim J, Wang X, Zhou S, Xu M, Wang S, Zhu Z, Thai T, Takahashi C, Wang Y, Neve R, Stinson S, Tamayo P, Watanabe H, Kirschmeier P, Wong K, Barbie D. Overcoming Resistance to Dual Innate Immune and MEK Inhibition Downstream of KRAS. Cancer Cell 2018, 34: 439-452.e6. PMID: 30205046, PMCID: PMC6422029, DOI: 10.1016/j.ccell.2018.08.009.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAMP-Activated Protein Kinase KinasesAMP-Activated Protein KinasesAnimalsAntineoplastic Agents, ImmunologicalCarcinoma, Non-Small-Cell LungCell Line, TumorDisease Models, AnimalDrug Resistance, NeoplasmHEK293 CellsHumansImmunity, InnateInsulin-Like Growth Factor ILung NeoplasmsMiceMice, TransgenicMitogen-Activated Protein Kinase KinasesPhosphoproteinsProtein Kinase InhibitorsProtein Serine-Threonine KinasesProto-Oncogene Proteins p21(ras)Transcription FactorsYAP-Signaling ProteinsConceptsGenetically engineered mouse modelsMediators of acquired resistanceDownstream of KRASBET inhibitor JQ1Effective therapeutic strategyTumor shrinkageTargeted therapyIntermittent treatmentYAP1 signalingMouse modelPathway inhibitionBET inhibitionTherapeutic strategiesInhibitor JQ1YAP1 upregulationOncogenic KRASBET inhibitorsOvercome resistancePromoter acetylationIntrinsic resistancePotential translationKRASMEKInnateInhibition
2016
Phase separation of signaling molecules promotes T cell receptor signal transduction
Su X, Ditlev JA, Hui E, Xing W, Banjade S, Okrut J, King DS, Taunton J, Rosen MK, Vale RD. Phase separation of signaling molecules promotes T cell receptor signal transduction. Science 2016, 352: 595-599. PMID: 27056844, PMCID: PMC4892427, DOI: 10.1126/science.aad9964.Peer-Reviewed Original ResearchMeSH KeywordsActinsAdaptor Proteins, Signal TransducingFluorescence Recovery After PhotobleachingHumansJurkat CellsMembrane ProteinsMitogen-Activated Protein Kinase KinasesPhosphorylationPolymerizationReceptors, Antigen, T-CellSignal TransductionT-LymphocytesConceptsT cell receptor (TCR) signal transductionHuman Jurkat T cellsActin filament assemblySubmicrometer-sized clustersReceptor signal transductionT cell receptor activationProtein phase separationJurkat T cellsCell receptor activationCell surface receptorsTCR phosphorylationActin regulatorsActin assemblySignal transductionFilament assemblyBiochemical compartmentsFunctional consequencesSurface receptorsModel membranesReceptor activationAssemblyActivationTransductionKinasePhosphorylation
2015
MEK Inhibitor PD-0325901 Overcomes Resistance to PI3K/mTOR Inhibitor PF-5212384 and Potentiates Antitumor Effects in Human Head and Neck Squamous Cell Carcinoma
Mohan S, Vander Broek R, Shah S, Eytan D, Pierce M, Carlson S, Coupar J, Zhang J, Cheng H, Chen Z, Van Waes C. MEK Inhibitor PD-0325901 Overcomes Resistance to PI3K/mTOR Inhibitor PF-5212384 and Potentiates Antitumor Effects in Human Head and Neck Squamous Cell Carcinoma. Clinical Cancer Research 2015, 21: 3946-3956. PMID: 25977343, PMCID: PMC4558307, DOI: 10.1158/1078-0432.ccr-14-3377.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsBenzamidesCarcinoma, Squamous CellCell Line, TumorCell ProliferationCell SurvivalCell Transformation, NeoplasticCytokinesDiphenylamineDisease Models, AnimalDrug Resistance, NeoplasmDrug SynergismGene ExpressionGenes, ReporterHead and Neck NeoplasmsHumansInflammation MediatorsMitogen-Activated Protein Kinase KinasesMorpholinesNF-kappa BPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsPhosphorylationProtein Kinase InhibitorsSignal TransductionSquamous Cell Carcinoma of Head and NeckTOR Serine-Threonine KinasesTranscription Factor AP-1Transcriptional ActivationTriazinesXenograft Model Antitumor AssaysElevated circulating tissue inhibitor of metalloproteinase 1 (TIMP‐1) levels are associated with neuroendocrine differentiation in castration resistant prostate cancer
Gong Y, Chippada‐Venkata U, Galsky M, Huang J, Oh W. Elevated circulating tissue inhibitor of metalloproteinase 1 (TIMP‐1) levels are associated with neuroendocrine differentiation in castration resistant prostate cancer. The Prostate 2015, 75: 616-627. PMID: 25560638, DOI: 10.1002/pros.22945.Peer-Reviewed Original ResearchMeSH KeywordsCell DifferentiationCell Line, TumorChromogranin AHumansInterleukin-6MaleMitogen-Activated Protein Kinase KinasesNeuroendocrine CellsNF-kappa BProstate-Specific AntigenProstatic Neoplasms, Castration-ResistantTissue Inhibitor of Metalloproteinase-1ConceptsCastration-resistant prostate cancerTIMP-1 levelsTIMP-1 expressionTIMP-1 mRNA expressionResistant prostate cancerNeuroendocrine differentiationTIMP-1 overexpressionProstate cancerLNCaP cellsTIMP-1PC-3MAndrogen receptorChromogranin APC-3Elevated plasma TIMP-1 levelsInhibits matrix metalloproteinase (MMPTumor tissuesMetastatic castration-resistant prostate cancerElevated TIMP-1 expressionCastration resistant prostate cancerSerum TIMP-1 levelsPlasma TIMP-1 levelsAndrogen-sensitive LNCaP cellsAssociated with neuroendocrine differentiationLevels of TIMP-1
2014
Combined BRAF (Dabrafenib) and MEK Inhibition (Trametinib) in Patients With BRAFV600-Mutant Melanoma Experiencing Progression With Single-Agent BRAF Inhibitor
Johnson DB, Flaherty KT, Weber JS, Infante JR, Kim KB, Kefford RF, Hamid O, Schuchter L, Cebon J, Sharfman WH, McWilliams RR, Sznol M, Lawrence DP, Gibney GT, Burris HA, Falchook GS, Algazi A, Lewis K, Long GV, Patel K, Ibrahim N, Sun P, Little S, Cunningham E, Sosman JA, Daud A, Gonzalez R. Combined BRAF (Dabrafenib) and MEK Inhibition (Trametinib) in Patients With BRAFV600-Mutant Melanoma Experiencing Progression With Single-Agent BRAF Inhibitor. Journal Of Clinical Oncology 2014, 32: 3697-3704. PMID: 25287827, PMCID: PMC4226803, DOI: 10.1200/jco.2014.57.3535.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAgedAged, 80 and overAntineoplastic Combined Chemotherapy ProtocolsDisease ProgressionDisease-Free SurvivalFemaleHumansImidazolesMaleMelanomaMiddle AgedMitogen-Activated Protein Kinase KinasesMutationOximesProtein Kinase InhibitorsProto-Oncogene Proteins B-rafPyridonesPyrimidinonesConceptsObjective response rateProgression-free survivalMedian progression-free survivalEfficacy of dabrafenibBRAF inhibitor treatmentBRAF inhibitorsOpen-label phase I/II studyInhibitor treatmentPhase I/II studySingle-agent BRAF inhibitorsMEK inhibitionBRAF inhibitor-resistant melanomaBRAF inhibitor monotherapyMedian overall survivalModest clinical efficacyBRAF inhibitor therapyEarly clinical studiesDabrafenib monotherapyInitial therapyStable diseaseII studyInhibitor monotherapyOverall survivalInhibitor therapyStudy enrollmentPrognostic Biomarkers in Phase II Trial of Cetuximab-Containing Induction and Chemoradiation in Resectable HNSCC: Eastern Cooperative Oncology Group E2303
Psyrri A, Lee JW, Pectasides E, Vassilakopoulou M, Kosmidis EK, Burtness BA, Rimm DL, Wanebo HJ, Forastiere AA. Prognostic Biomarkers in Phase II Trial of Cetuximab-Containing Induction and Chemoradiation in Resectable HNSCC: Eastern Cooperative Oncology Group E2303. Clinical Cancer Research 2014, 20: 3023-3032. PMID: 24700741, PMCID: PMC4049169, DOI: 10.1158/1078-0432.ccr-14-0113.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntibodies, Monoclonal, HumanizedAntineoplastic Combined Chemotherapy ProtocolsBiomarkers, TumorCarboplatinCarcinoma, Squamous CellCetuximabChemoradiotherapyDisease-Free SurvivalDrug Resistance, NeoplasmFemaleFluorescent Antibody TechniqueHead and Neck NeoplasmsHumansInduction ChemotherapyKaplan-Meier EstimateMaleMiddle AgedMitogen-Activated Protein Kinase KinasesPaclitaxelPhosphatidylinositol 3-KinasesPrognosisProportional Hazards ModelsProto-Oncogene Proteins c-aktras ProteinsSignal TransductionSquamous Cell Carcinoma of Head and NeckTissue Array AnalysisConceptsProgression-free survivalEvent-free survivalPhase II trialOverall survivalII trialTissue microarrayStage III/IV headMultivariable Cox proportional hazards modelsMultivariable Cox regression analysisNeck squamous cell cancerRAS/MAPK/ERKCox proportional hazards modelInsulin-like growth factor 1 receptorLarge prospective studiesCox regression analysisInferior overall survivalKaplan-Meier methodSquamous cell cancerLog-rank testGrowth factor 1 receptorProportional hazards modelPI3K/Akt pathwayFactor 1 receptorPI3K/AktEGF receptor
2013
Cdc42 Deficiency Causes Ciliary Abnormalities and Cystic Kidneys
Choi SY, Chacon-Heszele MF, Huang L, McKenna S, Wilson FP, Zuo X, Lipschutz JH. Cdc42 Deficiency Causes Ciliary Abnormalities and Cystic Kidneys. Journal Of The American Society Of Nephrology 2013, 24: 1435-1450. PMID: 23766535, PMCID: PMC3752951, DOI: 10.1681/asn.2012121236.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosiscdc42 GTP-Binding ProteinCell ProliferationCiliaDisease Models, AnimalFibrosisIn Vitro TechniquesKidney Diseases, CysticKidney Tubules, CollectingKidney Tubules, DistalMiceMice, KnockoutMice, TransgenicMitogen-Activated Protein Kinase KinasesPhenotypeSignal TransductionVesicular Transport ProteinsZebrafishZebrafish ProteinsConceptsCiliary proteinsSynergistic genetic interactionMitogen-activated protein kinase activationSmall GTPase Cdc42Role of Cdc42Protein kinase activationKnockdown of Cdc42Trafficking complexGTPase Cdc42Genetic interactionsSec10 knockdownPolycystic kidney diseaseCyst cellsCdc42 knockdownPrimary ciliaPhotoreceptor ciliaCdc42Kinase activationExocystMAPK activationCiliogenesisSec10Same pathwayPathways resultsCdc42 deficiencyBDNF Regulates Atypical PKC at Spinal Synapses to Initiate and Maintain a Centralized Chronic Pain State
Melemedjian OK, Tillu DV, Asiedu MN, Mandell EK, Moy JK, Blute VM, Taylor CJ, Ghosh S, Price TJ. BDNF Regulates Atypical PKC at Spinal Synapses to Initiate and Maintain a Centralized Chronic Pain State. Molecular Pain 2013, 9: 1744-8069-9-12. PMID: 23510079, PMCID: PMC3608966, DOI: 10.1186/1744-8069-9-12.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBrain-Derived Neurotrophic FactorCalcium-Calmodulin-Dependent Protein Kinase Type 2Cerebral CortexChronic PainEukaryotic Initiation Factor-4FExtracellular Signal-Regulated MAP KinasesMaleMAP Kinase Signaling SystemMiceMice, Inbred ICRMitogen-Activated Protein Kinase KinasesModels, BiologicalPhosphorylationPosterior Horn CellsProtein BiosynthesisProtein Kinase CProtein TransportSynapsesTime FactorsTOR Serine-Threonine KinasesConceptsChronic pain statesPain statesPersistent nociceptive sensitizationSpinal synapsesChronic painNociceptive sensitizationPotential therapeutic targetImportant medical problemNeurotrophic factorBDNF regulationPersistent sensitizationBDNFTherapeutic targetMedical problemsPainNovel therapeuticsEssential mediatorSensitizationPermanent reversalSynapsesMolecular linkPKMζKey regulator
2011
Concurrent loss of the PTEN and RB1 tumor suppressors attenuates RAF dependence in melanomas harboring V600EBRAF
Xing F, Persaud Y, Pratilas C, Taylor B, Janakiraman M, She Q, Gallardo H, Liu C, Merghoub T, Hefter B, Dolgalev I, Viale A, Heguy A, De Stanchina E, Cobrinik D, Bollag G, Wolchok J, Houghton A, Solit D. Concurrent loss of the PTEN and RB1 tumor suppressors attenuates RAF dependence in melanomas harboring V600EBRAF. Oncogene 2011, 31: 446-457. PMID: 21725359, PMCID: PMC3267014, DOI: 10.1038/onc.2011.250.Peer-Reviewed Original ResearchConceptsHeterogeneity of clinical outcomesSpectrum of genetic alterationsLoss of p16INK4aDiversity of clinical phenotypesLoss of RB1Prevent tumor formationMEK-selective inhibitorsRB1 tumor suppressorV600EBRAF mutationRB1 alterationsMutant BRAFClinical benefitMitogen-activated protein kinase pathwayClinical outcomesBRAF signalingGenetic alterationsGenomic alterationsOncogenic BRAFClinical phenotypePTEN inactivationProtein kinase pathwayCritical oncogenesTumor formationBRAFHuman cancersHigh-throughput mutation profiling of CTCL samples reveals KRAS and NRAS mutations sensitizing tumors toward inhibition of the RAS/RAF/MEK signaling cascade
Kießling M, Oberholzer PA, Mondal C, Karpova MB, Zipser MC, Lin WM, Girardi M, MacConaill LE, Kehoe SM, Hatton C, French LE, Garraway LA, Polier G, Süss D, Klemke CD, Krammer PH, Gülow K, Dummer R. High-throughput mutation profiling of CTCL samples reveals KRAS and NRAS mutations sensitizing tumors toward inhibition of the RAS/RAF/MEK signaling cascade. Blood 2011, 117: 2433-2440. PMID: 21209378, PMCID: PMC3952811, DOI: 10.1182/blood-2010-09-305128.Peer-Reviewed Original ResearchMeSH KeywordsBiopsyHigh-Throughput Screening AssaysHumansLymphoma, T-Cell, CutaneousMitogen-Activated Protein Kinase KinasesMutationMycosis FungoidesNeoplasm StagingProtein Kinase InhibitorsProto-Oncogene ProteinsProto-Oncogene Proteins p21(ras)raf Kinasesras ProteinsSezary SyndromeSignal TransductionConceptsCutaneous T-cell lymphomaStage IV patientsHUT78 cellsIV patientsPleomorphic cutaneous T-cell lymphomaHigh-throughput mutation profilingMEK inhibitorsCTCL cell line Hut78T-cell lymphomaRAS/RAF/MEKCTCL cell linesOncogenic mutationsCommon oncogenic mutationsCTCL patientsOverall survivalSézary syndromeMycosis fungoidesBiopsy specimensPatients profitPreclinical resultsMEK inhibitor U0126NRAS mutationsLymphoid cellsCTCL samplesRAS mutations
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