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
Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas
Krauthammer M, Kong Y, Bacchiocchi A, Evans P, Pornputtapong N, Wu C, McCusker JP, Ma S, Cheng E, Straub R, Serin M, Bosenberg M, Ariyan S, Narayan D, Sznol M, Kluger HM, Mane S, Schlessinger J, Lifton RP, Halaban R. Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas. Nature Genetics 2015, 47: 996-1002. PMID: 26214590, PMCID: PMC4916843, DOI: 10.1038/ng.3361.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic AgentsBenzimidazolesDNA Mutational AnalysisDrug Resistance, NeoplasmExomeGenetic Association StudiesGenetic Predisposition to DiseaseHumansInhibitory Concentration 50Kaplan-Meier EstimateLoss of HeterozygosityMaleMelanomaMutation, MissenseNeurofibromin 1Ras ProteinsSequence Analysis, RNASkin NeoplasmsSunlightTumor Cells, CulturedDownregulation 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 kinaseJAK1Downregulation
2014
Identification 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
Preexisting 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
2009
Integrative Analysis of Epigenetic Modulation in Melanoma Cell Response to Decitabine: Clinical Implications
Halaban R, Krauthammer M, Pelizzola M, Cheng E, Kovacs D, Sznol M, Ariyan S, Narayan D, Bacchiocchi A, Molinaro A, Kluger Y, Deng M, Tran N, Zhang W, Picardo M, Enghild JJ. Integrative Analysis of Epigenetic Modulation in Melanoma Cell Response to Decitabine: Clinical Implications. PLOS ONE 2009, 4: e4563. PMID: 19234609, PMCID: PMC2642998, DOI: 10.1371/journal.pone.0004563.Peer-Reviewed Original ResearchConceptsDNA damage responseMelanoma cell responseDamage responseGene expressionIntegrative analysisDifferential gene expressionMelanoma cell strainsGene expression profilesDNA promoter methylationP53-independent mannerHistone modificationsImproved combination therapiesEpigenetic modifiersTGFbeta pathwayBioinformatics analysisProtein stabilityEpigenetic modulationResistant melanoma cellsExpression profilesGrowth arrestPromoter methylationCancer cellsCell strainsProteasome inhibitorsPTEN mutations