2016
AMPK promotes tolerance to Ras pathway inhibition by activating autophagy
Sanduja S, Feng Y, Mathis RA, Sokol ES, Reinhardt F, Halaban R, Gupta PB. AMPK promotes tolerance to Ras pathway inhibition by activating autophagy. Oncogene 2016, 35: 5295-5303. PMID: 27041569, PMCID: PMC6086350, DOI: 10.1038/onc.2016.70.Peer-Reviewed Original ResearchConceptsCellular energy sensor AMPEnergy sensor AMPPathway inhibitorTargeted inhibitorsRas-Raf pathwayDrug-tolerant cellsPathway inhibitionOncogenic RasProtein kinaseRaf signalingRas pathway inhibitionReduced growthAMPKAutophagyPathway mutationsCancer cellsResistant cellsKey mechanismPathwayInhibitorsCellsToleranceKinaseSignalingInhibition
2015
Downregulation of the Ubiquitin Ligase RNF125 Underlies Resistance of Melanoma Cells to BRAF Inhibitors via JAK1 Deregulation
Kim H, Frederick DT, Levesque MP, Cooper ZA, Feng Y, Krepler C, Brill L, Samuels Y, Hayward NK, Perlina A, Piris A, Zhang T, Halaban R, Herlyn MM, Brown KM, Wargo JA, Dummer R, Flaherty KT, Ronai Z. Downregulation of the Ubiquitin Ligase RNF125 Underlies Resistance of Melanoma Cells to BRAF Inhibitors via JAK1 Deregulation. Cell Reports 2015, 11: 1458-1473. PMID: 26027934, PMCID: PMC4681438, DOI: 10.1016/j.celrep.2015.04.049.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell Line, TumorChromatography, LiquidDown-RegulationDrug Resistance, NeoplasmEnzyme InhibitorsFemaleHeterograftsHumansImmunoblottingImmunohistochemistryImmunoprecipitationJanus Kinase 1Mass SpectrometryMelanomaMiceMice, NudeProto-Oncogene Proteins B-rafRNA, Small InterferingTransfectionUbiquitin-Protein LigasesConceptsBRAF inhibitorsRTK expressionReceptor tyrosine kinasesRemarkable clinical responsesBRAFi-resistant melanomasInhibition of JAK1BRAFi-resistant tumorsClinical responseCombination therapyMost tumorsBRAF mutationsTumor specimensVivo xenograftsBRAFi resistanceMelanoma cellsElevated expressionMelanomaEGFRAdaptive resistanceTumorsRNF125MITF expressionTyrosine kinaseJAK1DownregulationPDK1 and SGK3 Contribute to the Growth of BRAF-Mutant Melanomas and Are Potential Therapeutic Targets
Scortegagna M, Lau E, Zhang T, Feng Y, Sereduk C, Yin H, De SK, Meeth K, Platt JT, Langdon CG, Halaban R, Pellecchia M, Davies MA, Brown K, Stern DF, Bosenberg M, Ronai ZA. PDK1 and SGK3 Contribute to the Growth of BRAF-Mutant Melanomas and Are Potential Therapeutic Targets. Cancer Research 2015, 75: 1399-1412. PMID: 25712345, PMCID: PMC4383687, DOI: 10.1158/0008-5472.can-14-2785.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBenzoatesBridged Bicyclo Compounds, HeterocyclicCell Line, TumorDrug Screening Assays, AntitumorG1 Phase Cell Cycle CheckpointsHumansImmediate-Early ProteinsIndazolesLymphatic MetastasisMelanomaMice, KnockoutMolecular Targeted TherapyProtein Kinase InhibitorsProtein Serine-Threonine KinasesProto-Oncogene Proteins B-rafPyrimidinesPyruvate Dehydrogenase Acetyl-Transferring KinaseSkinSkin NeoplasmsConceptsPDK1 inhibitionAGC kinase familySynthetic lethal screenCell cycle arrestPhase cell cycle arrestPigmentation genesPDK1 activityG1 phase cell cycle arrestSuppress melanoma growthKinase familyTherapeutic targetMelanoma growthPDK1PTEN genotypePI3KMelanoma developmentPotential therapeutic targetK inhibitionPharmacologic inhibitionDevelopment of melanomaPan-PI3K inhibitionBRAF-mutant melanomaSGK3GenesMelanoma cells
2014
Rare SF3B1 R625 mutations in cutaneous melanoma
Kong Y, Krauthammer M, Halaban R. Rare SF3B1 R625 mutations in cutaneous melanoma. Melanoma Research 2014, 24: 332-334. PMID: 24709888, PMCID: PMC4101881, DOI: 10.1097/cmr.0000000000000071.Peer-Reviewed Original ResearchIdentification of PLX4032‐resistance mechanisms and implications for novel RAF inhibitors
Choi J, Landrette SF, Wang T, Evans P, Bacchiocchi A, Bjornson R, Cheng E, Stiegler AL, Gathiaka S, Acevedo O, Boggon TJ, Krauthammer M, Halaban R, Xu T. Identification of PLX4032‐resistance mechanisms and implications for novel RAF inhibitors. Pigment Cell & Melanoma Research 2014, 27: 253-262. PMID: 24283590, PMCID: PMC4065135, DOI: 10.1111/pcmr.12197.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceCell Line, TumorCell ProliferationDNA Transposable ElementsDrug Resistance, NeoplasmHumansIndolesMAP Kinase Signaling SystemMelanomaModels, MolecularMolecular Sequence DataMutagenesis, InsertionalMutant ProteinsMutationProtein Kinase InhibitorsProto-Oncogene Proteins B-rafSulfonamidesVemurafenibConceptsBRAF mutationsNovel BRAF mutationBRAF inhibitorsNext-generation BRAF inhibitorsPLX4032-resistant melanoma cellsMelanoma cellsMelanoma patient survivalHuman prostate cancerBRAF mutant cellsWhole-exome sequencingMelanoma patientsPatient survivalClinical trialsProstate cancerRAF inhibitorsOncogenic mutationsNew screening approachRelevant aberrationsInhibitorsCellsMutationsScreening approachNovel RAF inhibitorsPatientsPLX8394
2012
Integrated analysis of tumor samples sheds light on tumor heterogeneity.
Parisi F, Micsinai M, Strino F, Ariyan S, Narayan D, Bacchiocchi A, Cheng E, Xu F, Li P, Kluger H, Halaban R, Kluger Y. Integrated analysis of tumor samples sheds light on tumor heterogeneity. The Yale Journal Of Biology And Medicine 2012, 85: 347-61. PMID: 23012583, PMCID: PMC3447199.Peer-Reviewed Original ResearchMeSH KeywordsCell Line, TumorChromosome MappingChromosomes, HumanDNA Copy Number VariationsEvolution, MolecularGene Expression ProfilingGene Expression Regulation, NeoplasticGenes, NeoplasmHumansIntercellular Signaling Peptides and ProteinsKaryotypingMelanomaMutationOligonucleotide Array Sequence AnalysisPolymorphism, Single NucleotideProto-Oncogene Proteins B-rafConceptsHigh-throughput profilingGene expression levelsExpression levelsDifferent gene expression levelsGene expression profilingCopy number analysisExpression profilingSNP arrayPathway analysisCopy number statusWnt pathwayTumor samplesNumber alteration profilesTumor heterogeneityTumor evolutionCopy number alteration profilesGenomic aberrationsIntegrated analysisCell linesTumor subclonesNumber analysisNumber statusProfilingDriver mutationsRecurrent associationExome sequencing identifies recurrent somatic RAC1 mutations in melanoma
Krauthammer M, Kong Y, Ha BH, Evans P, Bacchiocchi A, McCusker J, Cheng E, Davis MJ, Goh G, Choi M, Ariyan S, Narayan D, Dutton-Regester K, Capatana A, Holman EC, Bosenberg M, Sznol M, Kluger HM, Brash DE, Stern DF, Materin MA, Lo RS, Mane S, Ma S, Kidd KK, Hayward NK, Lifton RP, Schlessinger J, Boggon TJ, Halaban R. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nature Genetics 2012, 44: 1006-1014. PMID: 22842228, PMCID: PMC3432702, DOI: 10.1038/ng.2359.Peer-Reviewed Original ResearchMeSH KeywordsAgedAged, 80 and overCase-Control StudiesDNA Mutational AnalysisExomeFemaleGene FrequencyGenetic Predisposition to DiseaseHumansMaleMelanomaMiddle AgedModels, MolecularMutationProto-Oncogene Proteins B-rafProto-Oncogene Proteins p21(ras)Rac1 GTP-Binding ProteinSequence Analysis, DNASkin NeoplasmsUveal NeoplasmsConceptsSun-exposed melanomasPreexisting MEK1 Exon 3 Mutations in V600E/KBRAF Melanomas Do Not Confer Resistance to BRAF Inhibitors
Shi H, Moriceau G, Kong X, Koya RC, Nazarian R, Pupo GM, Bacchiocchi A, Dahlman KB, Chmielowski B, Sosman JA, Halaban R, Kefford RF, Long GV, Ribas A, Lo RS. Preexisting MEK1 Exon 3 Mutations in V600E/KBRAF Melanomas Do Not Confer Resistance to BRAF Inhibitors. Cancer Discovery 2012, 2: 414-424. PMID: 22588879, PMCID: PMC3594852, DOI: 10.1158/2159-8290.cd-12-0022.Peer-Reviewed Original ResearchConceptsBRAF inhibitorsActivating mutationsObjective tumor responseMEK1/2 inhibitorMEK1 mutationsP-ERK1/2 levelsBRAF-mutant melanomaMelanoma cell linesAdvanced melanomaAntitumor responseExon 3 mutationsTumor responseDisease progressionMelanomaBRAFi resistanceDrug sensitivitySignificant alterationsPatientsCell linesInhibitorsBaselineMutationsExon 3Widespread use
2011
In Vivo Identification of Tumor- Suppressive PTEN ceRNAs in an Oncogenic BRAF-Induced Mouse Model of Melanoma
Karreth FA, Tay Y, Perna D, Ala U, Tan SM, Rust AG, DeNicola G, Webster KA, Weiss D, Perez-Mancera PA, Krauthammer M, Halaban R, Provero P, Adams DJ, Tuveson DA, Pandolfi PP. In Vivo Identification of Tumor- Suppressive PTEN ceRNAs in an Oncogenic BRAF-Induced Mouse Model of Melanoma. Cell 2011, 147: 382-395. PMID: 22000016, PMCID: PMC3236086, DOI: 10.1016/j.cell.2011.09.032.Peer-Reviewed Original ResearchConceptsMicroRNA recognition elementsLow PTEN levelsPTEN protein levelsZEB2 expressionBeauty insertional mutagenesisMicroRNA decoysPI3K/Akt pathwayLoss of PTENCeRNA activityInsertional mutagenesisZeb2 transcriptTumor suppressorCell transformationCeRNAsPTEN levelsAkt pathwayFunctional roleMRNA transcriptsSignificant enrichmentZEB2 mRNAProtein levelsMouse modelCeRNATranscriptsPTEN
2010
Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032
Rubinstein JC, Sznol M, Pavlick AC, Ariyan S, Cheng E, Bacchiocchi A, Kluger HM, Narayan D, Halaban R. Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032. Journal Of Translational Medicine 2010, 8: 67. PMID: 20630094, PMCID: PMC2917408, DOI: 10.1186/1479-5876-8-67.Peer-Reviewed Original ResearchConceptsV600K mutationsClinical trialsBRAF V600E/K mutationK mutationPotential therapeutic responseMutant BRAF inhibitorsBRAF inhibitor PLX4032BRAF V600K mutationMelanoma patientsTherapeutic responseBRAF mutationsPatientsV600E mutationInhibitor PLX4032BRAF kinasePLX4032TrialsCommon mutationsMutationsMelanomaIncidencePLX4032, a selective BRAFV600E kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAFWT melanoma cells
Halaban R, Zhang W, Bacchiocchi A, Cheng E, Parisi F, Ariyan S, Krauthammer M, McCusker JP, Kluger Y, Sznol M. PLX4032, a selective BRAFV600E kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAFWT melanoma cells. Pigment Cell & Melanoma Research 2010, 23: 190-200. PMID: 20149136, PMCID: PMC2848976, DOI: 10.1111/j.1755-148x.2010.00685.x.Peer-Reviewed Original ResearchConceptsMelanoma cellsTumor cellsMelanoma tumor cellsPrimary melanoma cellsMetastatic tumor cellsStatus of mutationsClinical responseRate of proliferationAdvanced lesionsInhibitor PLX4032Kinase inhibitorsPLX4032ERK pathwayCell migrationNRASDownstream effectorsCell adherenceERK1/2CellsProliferationCell cycle controlMobility of cellsActive ERK1/2Therapy