Featured Publications
Phosphoproteomic Screen Identifies Potential Therapeutic Targets in Melanoma
Tworkoski K, Singhal G, Szpakowski S, Zito CI, Bacchiocchi A, Muthusamy V, Bosenberg M, Krauthammer M, Halaban R, Stern DF. Phosphoproteomic Screen Identifies Potential Therapeutic Targets in Melanoma. Molecular Cancer Research 2011, 9: 801-812. PMID: 21521745, PMCID: PMC3117976, DOI: 10.1158/1541-7786.mcr-10-0512.Peer-Reviewed Original ResearchMeSH KeywordsApoptosisCell Line, TumorCell MovementCell ProliferationErbB ReceptorsGene Expression Regulation, NeoplasticGene Knockdown TechniquesHEK293 CellsHumansInfant, NewbornMelanocytesMelanomaPhosphoproteinsPhosphorylationProteomicsReceptor Protein-Tyrosine KinasesReceptor, IGF Type 2RNA, Small InterferingSignal TransductionSkin NeoplasmsSTAT3 Transcription FactorConceptsTherapeutic targetReceptor tyrosine kinasesMelanoma cellsPotential therapeutic targetIdentifies potential therapeutic targetsActive receptor tyrosine kinasesTyrosine kinaseMelanoma cell migrationReceptor expressionBreast cancerAxl knockdownAutocrine circuitTherapeutic interventionsCancer subtypesReceptor tyrosine kinase activationTyrosine kinase activationNovel targetActivated receptorsAxlRNA knockdownMelanomaCell migrationHER3KnockdownIGF1RGenotype-Selective Combination Therapies for Melanoma Identified by High-Throughput Drug Screening
Held MA, Langdon CG, Platt JT, Graham-Steed T, Liu Z, Chakraborty A, Bacchiocchi A, Koo A, Haskins JW, Bosenberg MW, Stern DF. Genotype-Selective Combination Therapies for Melanoma Identified by High-Throughput Drug Screening. Cancer Discovery 2013, 3: 52-67. PMID: 23239741, PMCID: PMC3546137, DOI: 10.1158/2159-8290.cd-12-0408.Peer-Reviewed Original ResearchConceptsMutant BRAF melanomaCyclin-dependent kinase inhibitorBRAF melanomaSmall molecule inhibitorsHigh-throughput drug screeningDrug screeningEGF receptorCombination therapyDrug combinationsMelanoma culturesContext of genotypePairwise combinationsResistance phenotypeCombinatorial drug screeningUnique treatment regimensCombination of statinsVivo xenograftsKinase inhibitorsMutant BRAFMutationsEfficacious drug combinationsPartial responseTreatment regimensRAS mutationsBRAF mutations
2018
Inhibition 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
2017
p90RSK Blockade Inhibits Dual BRAF and MEK Inhibitor-Resistant Melanoma by Targeting Protein Synthesis
Theodosakis N, Micevic G, Langdon CG, Ventura A, Means R, Stern DF, Bosenberg MW. p90RSK Blockade Inhibits Dual BRAF and MEK Inhibitor-Resistant Melanoma by Targeting Protein Synthesis. Journal Of Investigative Dermatology 2017, 137: 2187-2196. PMID: 28599981, PMCID: PMC6342201, DOI: 10.1016/j.jid.2016.12.033.Peer-Reviewed Original ResearchConceptsProtein synthesisRibosomal S6 kinase (RSK) familyPatient-derived melanoma cell linesDifferential protein expressionReverse phase protein arrayPhase protein arrayTranslation complexesKinase familyBI-D1870RSK inhibitorsMelanoma cell linesProtein arraysCell proliferationInhibitor treatmentProtein expressionCell linesNew targetsHuman melanoma patientsBRAF inhibitor vemurafenibA Computational Approach for Identifying Synergistic Drug Combinations
Gayvert KM, Aly O, Platt J, Bosenberg MW, Stern DF, Elemento O. A Computational Approach for Identifying Synergistic Drug Combinations. PLOS Computational Biology 2017, 13: e1005308. PMID: 28085880, PMCID: PMC5234777, DOI: 10.1371/journal.pcbi.1005308.Peer-Reviewed Original Research
2015
BRAF Inhibition Decreases Cellular Glucose Uptake in Melanoma in Association with Reduction in Cell Volume
Theodosakis N, Held MA, Marzuka-Alcala A, Meeth KM, Micevic G, Long GV, Scolyer RA, Stern DF, Bosenberg MW. BRAF Inhibition Decreases Cellular Glucose Uptake in Melanoma in Association with Reduction in Cell Volume. Molecular Cancer Therapeutics 2015, 14: 1680-1692. PMID: 25948295, PMCID: PMC4497841, DOI: 10.1158/1535-7163.mct-15-0080.Peer-Reviewed Original ResearchConceptsGlucose uptakeWeeks of treatmentBRAF kinase inhibitorsHigh response rateTumor cell deathMetastatic diseaseTransmembrane glucose transportMetastatic melanomaPatient cohortCellular glucose uptakeRadiographic changesVemurafenib treatmentBRAF inhibitorsBRAF inhibitionResponse rateEmission tomographyPhysiologic parametersNew protein translationKinase inhibitorsEarly responseImportant physiologic parametersCell volumeMelanomaVolume reductionCell volume regulationThe broad‐spectrum receptor tyrosine kinase inhibitor dovitinib suppresses growth of BRAF‐mutant melanoma cells in combination with other signaling pathway inhibitors
Langdon CG, Held MA, Platt JT, Meeth K, Iyidogan P, Mamillapalli R, Koo AB, Klein M, Liu Z, Bosenberg MW, Stern DF. The broad‐spectrum receptor tyrosine kinase inhibitor dovitinib suppresses growth of BRAF‐mutant melanoma cells in combination with other signaling pathway inhibitors. Pigment Cell & Melanoma Research 2015, 28: 417-430. PMID: 25854919, PMCID: PMC5215495, DOI: 10.1111/pcmr.12376.Peer-Reviewed Original ResearchConceptsBRAF-mutant melanomaBRAF inhibitorsCell linesCombination of dovitinibBRAF inhibitor treatmentBRAF mutant melanoma cellsBRAF inhibitor resistanceColorectal carcinoma cell linesBRAF-mutant melanoma cell linesMelanoma cell linesCarcinoma cell linesMetastatic melanomaEffective therapyWild-type BRAF cellsInhibitor treatmentAgent inhibitsPathway inhibitorDovitinibInhibitor resistanceMelanoma cellsMelanomaSecond agentInhibitorsTreatmentPDK1 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
2013
MERTK controls melanoma cell migration and survival and differentially regulates cell behavior relative to AXL
Tworkoski KA, Platt JT, Bacchiocchi A, Bosenberg M, Boggon TJ, Stern DF. MERTK controls melanoma cell migration and survival and differentially regulates cell behavior relative to AXL. Pigment Cell & Melanoma Research 2013, 26: 527-541. PMID: 23617806, PMCID: PMC3918898, DOI: 10.1111/pcmr.12110.Peer-Reviewed Original ResearchMeSH KeywordsAxl Receptor Tyrosine KinaseCdc42 GTP-Binding ProteinCell Line, TumorCell MovementCell ProliferationCell SurvivalC-Mer Tyrosine KinaseCytophotometryGene Expression ProfilingGene Expression Regulation, NeoplasticHEK293 CellsHumansMelanomaNeoplasm MetastasisOligonucleotide Array Sequence AnalysisPhosphorylationProto-Oncogene ProteinsReceptor Protein-Tyrosine KinasesSignal TransductionSkin NeoplasmsConceptsCell migrationCell behaviorMelanoma cellsAkt-dependent mannerShRNA-mediated knockdownDifferential cell behaviorDifferent transcriptional signaturesReceptor tyrosine kinase AXLMelanoma cell migrationMelanoma cell proliferationKinase domainTyrosine kinase AXLCell motilityTranscriptional signatureCell survivalColony formationCell proliferationOverexpression of AxlPossible therapeutic targetMelanoma pathogenesisNovel mutationsMerTKAxlTherapeutic targetMutations
2012
Exome 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 melanomas