2025
A Phase I/IB Trial of Pembrolizumab and Trametinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Enriched for KRAS Mutations
Riess J, Lara M, Luxardi G, de Rodas M, Shimoda M, Kelly K, Lara P, Beckett L, Monjazeb A, Schalper K, Maverakis E, Gandara D. A Phase I/IB Trial of Pembrolizumab and Trametinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Enriched for KRAS Mutations. JTO Clinical And Research Reports 2025, 100806. DOI: 10.1016/j.jtocrr.2025.100806.Peer-Reviewed Original ResearchNon-small cell lung cancerAdvanced non-small cell lung cancerMEK inhibitionAdverse eventsProgressive diseaseKRAS mutationsMyeloid-derived suppressor cellsTrametinib 2 mgDose-escalation studyPlatinum-based chemotherapyImmune cell alterationsTumor immune microenvironmentPhase 1 studyCell lung cancerHigh-parameter flow cytometryArm BEscalation studyPartial responseArm ASuppressor cellsImmune microenvironmentPembrolizumabTrametinibQuantitative immunofluorescenceLung cancer
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 ResearchConceptsOverall 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 ResearchConceptsMEK 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
Clinical Predictors of Survival in Patients With BRAFV600-Mutated Metastatic Melanoma Treated With Combined BRAF and MEK Inhibitors After Immune Checkpoint Inhibitors
Kahn A, Perry C, Etts K, Kluger H, Sznol M. Clinical Predictors of Survival in Patients With BRAFV600-Mutated Metastatic Melanoma Treated With Combined BRAF and MEK Inhibitors After Immune Checkpoint Inhibitors. The Oncologist 2023, 29: e507-e513. PMID: 37971411, PMCID: PMC10994263, DOI: 10.1093/oncolo/oyad300.Peer-Reviewed Original ResearchBRAF/MEK inhibitorsBRAF/MEK inhibitionImmune checkpoint inhibitorsBRAFV600E/K mutationsMEK inhibitorsCheckpoint inhibitorsClinical variablesMEK inhibitionRetrospective single-institution analysisIpilimumab/nivolumabFirst-line settingFirst-line therapyFirst-line treatmentMetastatic melanoma patientsLong-term outcomesPretreatment clinical variablesSingle-institution analysisStratification of patientsK mutationCombined BRAFECOG PSMedian OSRECIST 1.1Immunotherapy regimenClinical characteristicsCombined 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 ResearchConceptsPrimary 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 survival
2022
Clinical predictors of longer survival in patients with BRAFV600-mutated metastatic melanoma receiving immunotherapy prior to BRAF/MEK inhibition in the metastatic setting.
Kahn A, Perry C, Etts K, Kluger H, Sznol M. Clinical predictors of longer survival in patients with BRAFV600-mutated metastatic melanoma receiving immunotherapy prior to BRAF/MEK inhibition in the metastatic setting. Journal Of Clinical Oncology 2022, 40: 9555-9555. DOI: 10.1200/jco.2022.40.16_suppl.9555.Peer-Reviewed Original ResearchBRAF/MEKiFirst-line immunotherapyBRAF/MEK inhibitionBRAF V600Metastatic melanomaLonger survivalAdverse eventsMedian durationMost patientsBone metastasesClinical predictorsDisease progressionMEK inhibitionAdvanced BRAF V600ECOG PS 0Median ECOG PSFirst-line settingKaplan-Meier methodMost common sitePredictors of survivalECOG PSMedian LDHData cutoffMetastatic settingMedian survivalRASGRF1 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 ResearchConceptsLung 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 alterations
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 ResearchConceptsBladder tumorsUrothelial tumorsTherapeutic strategiesNovel therapeutic strategiesRational therapeutic strategiesPatient-derived modelsRaf/MEK/ERKClinical outcomesMEK/ERKTreatment optionsBladder cancerHeterogeneous diseaseMEK inhibitionTumorsUnique subsetFocal amplificationRAF inhibitorsCell linesRAF1Gene expression patternsActivationExpression patternsSignalingSubsetRaf1 activity
2020
Systemic Therapy for Brain Metastases: Melanoma
Weiss S, Kluger H. Systemic Therapy for Brain Metastases: Melanoma. 2020, 235-244. DOI: 10.1007/978-3-030-42958-4_16.Peer-Reviewed Original ResearchMelanoma brain metastasesIntracranial response ratesBrain metastasesClinical trialsResponse rateAnti-PD-1 monotherapyCentral nervous system metastasesExtracranial metastatic sitesNervous system metastasesSystemic therapy approachesMultiple clinical trialsSystemic therapySystemic treatmentAdvanced melanomaImmune checkpointsMetastatic sitesTherapeutic challengePatient survivalMetastatic melanomaExtracranial sitesStereotactic radiosurgeryMetastasisMutant BRAFSignificant causeMEK inhibition
2019
Dabrafenib and Trametinib for BRAF-Mutated Conjunctival Melanoma
Kim JM, Weiss S, Sinard JH, Pointdujour-Lim R. Dabrafenib and Trametinib for BRAF-Mutated Conjunctival Melanoma. Ocular Oncology And Pathology 2019, 6: 35-38. PMID: 32002403, PMCID: PMC6984155, DOI: 10.1159/000497473.Peer-Reviewed Original Research
2018
Amplification of Wild-type KRAS Imparts Resistance to Crizotinib in MET Exon 14 Mutant Non–Small Cell Lung Cancer
Bahcall M, Awad MM, Sholl LM, Wilson FH, Xu M, Wang S, Palakurthi S, Choi J, Ivanova E, Leonardi GC, Ulrich BC, Paweletz CP, Kirschmeier PT, Watanabe M, Baba H, Nishino M, Nagy RJ, Lanman RB, Capelletti M, Chambers ES, Redig AJ, VanderLaan PA, Costa DB, Imamura Y, Jänne P. Amplification of Wild-type KRAS Imparts Resistance to Crizotinib in MET Exon 14 Mutant Non–Small Cell Lung Cancer. Clinical Cancer Research 2018, 24: 5963-5976. PMID: 30072474, PMCID: PMC6279568, DOI: 10.1158/1078-0432.ccr-18-0876.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsCarcinoma, Non-Small-Cell LungCell Line, TumorCrizotinibDisease Models, AnimalDNA Copy Number VariationsDrug Resistance, NeoplasmExonsGene AmplificationGene Expression Regulation, NeoplasticHumansIn Situ Hybridization, FluorescenceLung NeoplasmsMiceModels, BiologicalMutationPhosphatidylinositol 3-KinasesPositron Emission Tomography Computed TomographyProtein Kinase InhibitorsProto-Oncogene Proteins c-metProto-Oncogene Proteins p21(ras)Signal TransductionXenograft Model Antitumor AssaysConceptsNon-small cell lung cancerMutant non-small cell lung cancerCell lung cancerPatient-derived cell linesCrizotinib resistanceLung cancerCell linesLong-term efficacyPI3KEGFR ligandsPI3K inhibitionCombination therapyEffective therapyMET inhibitorsSuperior efficacyPatient tumorsDrug combinationsMET inhibitionTherapeutic strategiesParental cell lineMEK inhibitionDrug resistanceRecurrent genetic eventsK inhibitionCompensatory inductionInhibition of isoprenylation synergizes with MAPK blockade to prevent growth in treatment‐resistant melanoma, colorectal, and lung cancer
Theodosakis N, Langdon CG, Micevic G, Krykbaeva I, Means RE, Stern DF, Bosenberg MW. Inhibition of isoprenylation synergizes with MAPK blockade to prevent growth in treatment‐resistant melanoma, colorectal, and lung cancer. Pigment Cell & Melanoma Research 2018, 32: 292-302. PMID: 30281931, PMCID: PMC6590911, DOI: 10.1111/pcmr.12742.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell Line, TumorCell ProliferationColorectal NeoplasmsDrug Resistance, NeoplasmDrug SynergismHumansHydroxymethylglutaryl-CoA Reductase InhibitorsLung NeoplasmsMaleMelanomaMevalonic AcidMice, NudeMitogen-Activated Protein KinasesPrenylationProtein Kinase InhibitorsProtein Processing, Post-TranslationalSignal TransductionConceptsUseful adjunctive therapyHMG-CoA reductase inhibitorsAnti-tumor effectsAdjunctive therapyInhibition of isoprenylationLung cancerMEK inhibitionReductase inhibitorsMAPK blockadeDriver mutationsAdditional studiesStatinsTherapyMelanomaTumorsVemurafenibMAPK pathwayDownstream metabolitesInhibitionMAPKAdjunctiveColorectalSelumetinibBlockadeCancer
2014
Comprehensive Genomic Profiling of Pancreatic Acinar Cell Carcinomas Identifies Recurrent RAF Fusions and Frequent Inactivation of DNA Repair Genes
Chmielecki J, Hutchinson K, Frampton G, Chalmers Z, Johnson A, Shi C, Elvin J, Ali S, Ross J, Basturk O, Balasubramanian S, Lipson D, Yelensky R, Pao W, Miller V, Klimstra D, Stephens P. Comprehensive Genomic Profiling of Pancreatic Acinar Cell Carcinomas Identifies Recurrent RAF Fusions and Frequent Inactivation of DNA Repair Genes. Cancer Discovery 2014, 4: 1398-1405. PMID: 25266736, DOI: 10.1158/2159-8290.cd-14-0617.Peer-Reviewed Original ResearchConceptsPancreatic acinar cell carcinomaInactivation of DNA repair genesComprehensive genomic profilingDNA repair genesGenomic alterationsSensitive to platinum-based therapyRepair genesMEK inhibitor trametinibPlatinum-based therapyAcinar cell carcinomaPancreatic cancer diagnosisSensitive to treatmentInhibitor trametinibCell carcinomaMEK inhibitionPancreatic cancerPARP inhibitorsGenomic profilingApproximately 1%Personalized therapyRecurrent rearrangementsFrequent inactivationTumorTherapeutic targetRAF genesCombined 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 enrollmentMEK Inhibition by Selumetinib Enhances the Antitumor and Anti-Metastatic Effects of Chemoradiation Therapy in Orthotopic Human Lung Cancer Models
Furutani S, Komaki R, Smith P, Jürgensmeier J, Takahashi O, Rabin T, Herbst R, O'Reilly M. MEK Inhibition by Selumetinib Enhances the Antitumor and Anti-Metastatic Effects of Chemoradiation Therapy in Orthotopic Human Lung Cancer Models. International Journal Of Radiation Oncology • Biology • Physics 2014, 90: s796. DOI: 10.1016/j.ijrobp.2014.05.2300.Peer-Reviewed Original Research
2012
Combined MEK and VEGFR Inhibition in Orthotopic Human Lung Cancer Models Results in Enhanced Inhibition of Tumor Angiogenesis, Growth, and Metastasis
Takahashi O, Komaki R, Smith PD, Jürgensmeier JM, Ryan A, Bekele BN, Wistuba II, Jacoby JJ, Korshunova MV, Biernacka A, Erez B, Hosho K, Herbst RS, O'Reilly MS. Combined MEK and VEGFR Inhibition in Orthotopic Human Lung Cancer Models Results in Enhanced Inhibition of Tumor Angiogenesis, Growth, and Metastasis. Clinical Cancer Research 2012, 18: 1641-1654. PMID: 22275507, PMCID: PMC3306446, DOI: 10.1158/1078-0432.ccr-11-2324.Peer-Reviewed Original ResearchMeSH KeywordsAngiogenesis InhibitorsAnimalsAntineoplastic Combined Chemotherapy ProtocolsBenzimidazolesCarcinoma, Non-Small-Cell LungCell Line, TumorCell ProliferationDisease ProgressionHumansLung NeoplasmsMaleMiceMice, NudeMitogen-Activated Protein KinasesMolecular Targeted TherapyNeovascularization, PathologicPaclitaxelProto-Oncogene ProteinsProto-Oncogene Proteins p21(ras)Quinazolinesras ProteinsReceptors, Vascular Endothelial Growth FactorXenograft Model Antitumor AssaysConceptsSignal-regulated kinase kinaseTumor cell proliferationCell proliferationReceptor tyrosine kinasesKinase kinaseAvailable MEK1/2 inhibitorHuman NSCLC cellsTyrosine kinaseVEGF receptor tyrosine kinasesERK phosphorylationNCI-H441MEK1/2 inhibitorApoptotic effectsAdjacent normal tissuesKinaseNSCLC cellsMEK inhibitionAntiangiogenic effectsSignalingOrthotopic human lung cancer modelAvailable potent inhibitorLung tumor growthPotent inhibitorTumor angiogenesisSelumetinib
2006
A Role for MAP Kinase Signaling in Behavioral Models of Depression and Antidepressant Treatment
Duman CH, Schlesinger L, Kodama M, Russell DS, Duman RS. A Role for MAP Kinase Signaling in Behavioral Models of Depression and Antidepressant Treatment. Biological Psychiatry 2006, 61: 661-670. PMID: 16945347, DOI: 10.1016/j.biopsych.2006.05.047.Peer-Reviewed Original ResearchMeSH KeywordsAnalysis of VarianceAniline CompoundsAnimalsAntidepressive AgentsBehavior, AnimalBenzamidesBrain-Derived Neurotrophic FactorDepressionDisease Models, AnimalDose-Response Relationship, DrugDrug InteractionsEnzyme InhibitorsHelplessness, LearnedHindlimb SuspensionMaleMiceMice, Inbred C57BLMice, KnockoutMitogen-Activated Protein Kinase KinasesMotor ActivitySignal TransductionSwimmingConceptsBrain-derived neurotrophic factorAntidepressant-like effectsAntidepressant treatmentSwim testBDNF heterozygous knockout miceDepressive-like behaviorDepressive-like phenotypeTail suspension testEffects of desipramineHeterozygous knockout miceDepressive behavioral phenotypeEffect of inhibitionRodent behavioral modelsMouse behavioral modelsHeterozygous gene deletionAntidepressant mechanismAcute administrationAcute blockadeNeurotrophic factorAntidepressant drugsSuspension testDepressive phenotypeKnockout miceMEK inhibitionMEK inhibitors
2002
Sphingosine-1-phosphate stimulates human Caco-2 intestinal epithelial proliferation via p38 activation and activates ERK by an independent mechanism
THAMILSELVAN V, LI W, SUMPIO BE, BASSON MD. Sphingosine-1-phosphate stimulates human Caco-2 intestinal epithelial proliferation via p38 activation and activates ERK by an independent mechanism. In Vitro Cellular & Developmental Biology - Animal 2002, 38: 246-253. PMID: 12197778, DOI: 10.1290/1071-2690(2002)038<0246:spshci>2.0.co;2.Peer-Reviewed Original ResearchConceptsExtracellular signal-regulated kinases 1Mitogen-activated protein kinaseMAP kinase kinaseCaco-2 proliferationMAPK activationHuman intestinal epithelial proliferationP38 activationCell typesSignal-regulated kinases 1Role of ERKMitogenic effectCaco-2 intestinal epithelial cellsIntracellular second messengerMEK inhibitionP38 MAPK activationCancer cell invasionKinase kinaseHuman Caco-2 intestinal epithelial cellsProtein kinaseStimulation of proliferationCell motilityIntestinal epithelial cell proliferationInhibitor PD98059ERK2ERK activation
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