2022
MET-induced CD73 restrains STING-mediated immunogenicity of EGFR-mutant lung cancer
Yoshida R, Saigi M, Tani T, Springer B, Shibata H, Kitajima S, Mahadevan N, Campisi M, Kim W, Kobayashi Y, Thai T, Haratani K, Yamamoto Y, Sundararaman S, Knelson E, Vajdi A, Canadas I, Uppaluri R, Paweletz C, Miret J, Lizotte P, Gokhale P, Jänne P, Barbie D. MET-induced CD73 restrains STING-mediated immunogenicity of EGFR-mutant lung cancer. Cancer Research 2022, 82: 4079-4092. PMID: 36066413, PMCID: PMC9627131, DOI: 10.1158/0008-5472.can-22-0770.Peer-Reviewed Original ResearchConceptsEGFR-mutant lung cancerEGFR-TKI-resistant cellsThird-generation EGFR tyrosine kinase inhibitorMET-amplifiedT cell responsesPemetrexed treatmentLung cancerCD8+ T cell immunogenicityEGFR-TKI treatment failureEGFR tyrosine kinase inhibitorsInhibit T cell responsesUpregulation of CD73Humanized mouse modelTyrosine kinase inhibitorsT-cell immunogenicityCell line studiesMET amplificationEGFR-TKIsTKI resistanceTreatment failureCancer immunogenicityCD73 inhibitionT cellsPemetrexedEnhanced immunogenicityCHMP2A regulates tumor sensitivity to natural killer cell-mediated cytotoxicity
Bernareggi D, Xie Q, Prager B, Yun J, Cruz L, Pham T, Kim W, Lee X, Coffey M, Zalfa C, Azmoon P, Zhu H, Tamayo P, Rich J, Kaufman D. CHMP2A regulates tumor sensitivity to natural killer cell-mediated cytotoxicity. Nature Communications 2022, 13: 1899. PMID: 35393416, PMCID: PMC8990014, DOI: 10.1038/s41467-022-29469-0.Peer-Reviewed Original ResearchConceptsResistance to NK cell-mediated cytotoxicityHead and neck squamous cell carcinomaNK cell-mediated killingNK cell-mediated cytotoxicityCell-mediated cytotoxicityCell-mediated killingTumor cellsGlioblastoma stem cellsNatural killerNK cellsIncreased NK cell-mediated killingMechanism of tumor immune escapeHead and neck squamous cell carcinoma modelResistance to NK cellsNeck squamous cell carcinomaApoptosis of NK cellsNK cell-mediated immunotherapyExtracellular vesiclesCell-mediated immunotherapyTumor immune escapeImmunodeficient mouse modelSquamous cell carcinomaNK cell migrationIncreased chemokine secretionHuman glioblastoma stem cells
2020
Mesenchymal and MAPK Expression Signatures Associate with Telomerase Promoter Mutations in Multiple Cancers
Stern J, Hibshman G, Hu K, Ferrara S, Costello J, Kim W, Tamayo P, Cech T, Huang F. Mesenchymal and MAPK Expression Signatures Associate with Telomerase Promoter Mutations in Multiple Cancers. Molecular Cancer Research 2020, 18: 1050-1062. PMID: 32276990, PMCID: PMC8020009, DOI: 10.1158/1541-7786.mcr-19-1244.Peer-Reviewed Original ResearchMeSH KeywordsCell Line, TumorChromatin ImmunoprecipitationEpithelial-Mesenchymal TransitionExtracellular Signal-Regulated MAP KinasesGene Expression ProfilingGene Expression Regulation, NeoplasticGene Regulatory NetworksHumansMutationNeoplasmsPromoter Regions, GeneticSequence Analysis, RNASmall Molecule LibrariesTelomeraseTumor MicroenvironmentConceptsCell linesAnalysis of cell linesAdherens junction protein E-cadherinKnock-down experimentsExpression signaturesRAS pathway inhibitorsInhibition of MEK1Promoter mutationsSensitivity to specific drugsCatalytic subunit of telomeraseJunction protein E-cadherinProtein E-cadherinSubunit of telomeraseInvestigational treatment approachesMesenchymal transcription factorsPan-cancer analysisCatalytic subunitEpithelial-to-mesenchymal transitionTranscription factorsCell line growthMutantsPathway effectorsTERT mRNA expressionMAPK signalingProliferative immortality
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 translationKRASMEKInnateInhibitionAn alternative splicing switch in FLNB promotes the mesenchymal cell state in human breast cancer
Li J, Choi P, Chaffer C, Labella K, Hwang J, Giacomelli A, Kim J, Ilic N, Doench J, Ly S, Dai C, Hagel K, Hong A, Gjoerup O, Goel S, Ge J, Root D, Zhao J, Brooks A, Weinberg R, Hahn W. An alternative splicing switch in FLNB promotes the mesenchymal cell state in human breast cancer. ELife 2018, 7: e37184. PMID: 30059005, PMCID: PMC6103745, DOI: 10.7554/elife.37184.Peer-Reviewed Original ResearchMeSH KeywordsAlternative SplicingAnimalsBase SequenceBreast NeoplasmsCell Line, TumorEpithelial-Mesenchymal TransitionExonsFemaleFilaminsGene Expression Regulation, NeoplasticGenome, HumanHumansHyaluronan ReceptorsMesenchymal Stem CellsMice, NudeNeoplasm ProteinsOpen Reading FramesProtein IsoformsReproducibility of ResultsRNA, MessengerRNA-Binding ProteinsConceptsEpithelial-to-mesenchymal transitionAlternative splicing of mRNA precursorsMesenchymal cell stateSplicing of mRNA precursorsCell statesRNA-binding proteinsAlternative splicing switchDysregulation of splicingBreast cancer patient samplesEMT gene signatureRegulation of epithelial-to-mesenchymal transitionCancer patient samplesInduce epithelial-to-mesenchymal transitionFOXC1 transcription factorRNA-seqAlternative splicingExpression screeningMRNA precursorsRegulating tumor cell plasticityRegulatory stepTranscription factorsSplicing switchProtein productionDiverse functionsIncreased tumorigenicityTumor innate immunity primed by specific interferon-stimulated endogenous retroviruses
Cañadas I, Thummalapalli R, Kim J, Kitajima S, Jenkins R, Christensen C, Campisi M, Kuang Y, Zhang Y, Gjini E, Zhang G, Tian T, Sen D, Miao D, Imamura Y, Thai T, Piel B, Terai H, Aref A, Hagan T, Koyama S, Watanabe M, Baba H, Adeni A, Lydon C, Tamayo P, Wei Z, Herlyn M, Barbie T, Uppaluri R, Sholl L, Sicinska E, Sands J, Rodig S, Wong K, Paweletz C, Watanabe H, Barbie D. Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses. Nature Medicine 2018, 24: 1143-1150. PMID: 30038220, PMCID: PMC6082722, DOI: 10.1038/s41591-018-0116-5.Peer-Reviewed Original ResearchConceptsInnate immune signalingSmall cell lung cancerEndogenous retrovirusesCell lung cancerPro-tumorigenic cytokinesImmune signalingAnalysis of cell linesCancer immunotherapyMesenchymal cell stateIFN-gTumor subpopulationsLung cancerLong terminal repeatHuman tumorsSPARC expressionMesenchymal markersTumorBi-directional transcriptionChromatin-modifying enzymesSTAT1 signalingCell linesCancerInnate immunityInducible SPARCS expressionGene promoterEx Vivo Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids
Jenkins R, Aref A, Lizotte P, Ivanova E, Stinson S, Zhou C, Bowden M, Deng J, Liu H, Miao D, He M, Walker W, Zhang G, Tian T, Cheng C, Wei Z, Palakurthi S, Bittinger M, Vitzthum H, Kim J, Merlino A, Quinn M, Venkataramani C, Kaplan J, Portell A, Gokhale P, Phillips B, Smart A, Rotem A, Jones R, Keogh L, Anguiano M, Stapleton L, Jia Z, Barzily-Rokni M, Cañadas I, Thai T, Hammond M, Vlahos R, Wang E, Zhang H, Li S, Hanna G, Huang W, Hoang M, Piris A, Eliane J, Stemmer-Rachamimov A, Cameron L, Su M, Shah P, Izar B, Thakuria M, LeBoeuf N, Rabinowits G, Gunda V, Parangi S, Cleary J, Miller B, Kitajima S, Thummalapalli R, Miao B, Barbie T, Sivathanu V, Wong J, Richards W, Bueno R, Yoon C, Miret J, Herlyn M, Garraway L, Van Allen E, Freeman G, Kirschmeier P, Lorch J, Ott P, Hodi F, Flaherty K, Kamm R, Boland G, Wong K, Dornan D, Paweletz C, Barbie D. Ex Vivo Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids. Cancer Discovery 2018, 8: cd-17-0833. PMID: 29101162, PMCID: PMC5809290, DOI: 10.1158/2159-8290.cd-17-0833.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic Agents, ImmunologicalCell Culture TechniquesCell Line, TumorCytokinesDrug Resistance, NeoplasmFlow CytometryHumansImmunohistochemistryImmunophenotypingMiceMicrofluidic Analytical TechniquesProgrammed Cell Death 1 ReceptorSpheroids, CellularTime-Lapse ImagingTumor Cells, CulturedConceptsImmune checkpoint blockadePD-1 blockadeResistance to PD-1 blockadeDevelopment of effective combination therapiesResistance to immune checkpoint blockadeResponse to ICBResponse to immune checkpoint blockadeImmunocompetent mouse tumor modelsTumor immune microenvironmentPrecision immuno-oncologyMyeloid cell populationsEffective combination therapyMouse tumor modelsProfile of secreted cytokinesEx vivo profileCheckpoint blockadePD-1Combination therapyImmune microenvironmentImmuno-oncologyTherapeutic combinationsTumor microenvironmentMurine modelTumor modelPatient specimens
2017
Exome Sequencing of African-American Prostate Cancer Reveals Loss-of-Function ERF Mutations
Huang F, Mosquera J, Garofalo A, Oh C, Baco M, Amin-Mansour A, Rabasha B, Bahl S, Mullane S, Robinson B, Aldubayan S, Khani F, Karir B, Kim E, Chimene-Weiss J, Hofree M, Romanel A, Osborne J, Kim J, Azabdaftari G, Woloszynska-Read A, Sfanos K, De Marzo A, Demichelis F, Gabriel S, Van Allen E, Mesirov J, Tamayo P, Rubin M, Powell I, Garraway L. Exome Sequencing of African-American Prostate Cancer Reveals Loss-of-Function ERF Mutations. Cancer Discovery 2017, 7: 973-983. PMID: 28515055, PMCID: PMC5836784, DOI: 10.1158/2159-8290.cd-16-0960.Peer-Reviewed Original ResearchConceptsProstate cancerRecurrent loss-of-function mutationsSystematic genome sequencingCastration-resistant prostate cancerLethal castration-resistant prostate cancerProstate cancer tumor suppressor geneCancer sequencing studiesCancer genome characterizationLoss-of-function mutationsIncreased anchorage-independent growthPrimary prostate cancerAfrican American menProstate cancer cohortAnchorage-independent growthTumor suppressor geneProstate cancer genesGene expression signaturesTranscriptional repressorGenomic characterizationSequencing studiesExome sequencingCancer genesAndrogen signalingGene mutationsCancer cohortDecomposing Oncogenic Transcriptional Signatures to Generate Maps of Divergent Cellular States
Kim J, Abudayyeh O, Yeerna H, Yeang C, Stewart M, Jenkins R, Kitajima S, Konieczkowski D, Medetgul-Ernar K, Cavazos T, Mah C, Ting S, Van Allen E, Cohen O, Mcdermott J, Damato E, Aguirre A, Liang J, Liberzon A, Alexe G, Doench J, Ghandi M, Vazquez F, Weir B, Tsherniak A, Subramanian A, Meneses-Cime K, Park J, Clemons P, Garraway L, Thomas D, Boehm J, Barbie D, Hahn W, Mesirov J, Tamayo P. Decomposing Oncogenic Transcriptional Signatures to Generate Maps of Divergent Cellular States. Cell Systems 2017, 5: 105-118.e9. PMID: 28837809, PMCID: PMC5639711, DOI: 10.1016/j.cels.2017.08.002.Peer-Reviewed Original ResearchConceptsCellular statesActivated downstream of RasDownstream of RasGenomic hallmarksIndividual tumor samplesCancer genomesRas pathwayPrecision medicine paradigmPharmacological perturbationsGenetic alterationsFunctional consequencesTranscriptional signatureSystematic sequenceReference mapEffective disease modelsOncogenic alterationsRasComplex landscapeTumor samplesDisease modelsTherapeutic strategiesMedicine paradigmGenomeAlterationsFunctional stateKEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer
Krall E, Wang B, Munoz D, Ilic N, Raghavan S, Niederst M, Yu K, Ruddy D, Aguirre A, Kim J, Redig A, Gainor J, Williams J, Asara J, Doench J, Janne P, Shaw A, McDonald R, Engelman J, Stegmeier F, Schlabach M, Hahn W. KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer. ELife 2017, 6: e18970. PMID: 28145866, PMCID: PMC5305212, DOI: 10.7554/elife.18970.Peer-Reviewed Original ResearchConceptsALK inhibitionMAPK signalingResponse to BRAFLoss of Keap1Presence of multiple inhibitorsAltering cell metabolismLung cancer cellsResistant to inhibitionClinical responseDeletion screeningTargeted therapyRTK/Ras/MAPK pathwayNegative regulatorReactive oxygen speciesCell metabolismCancer cellsBRAFCancerous inhibitorMultiple inhibitorsEGFRKEAP1 lossPromote survivalKeap1/Nrf2 pathwayOxygen speciesALK
2016
DiSCoVERing Innovative Therapies for Rare Tumors: Combining Genetically Accurate Disease Models with In Silico Analysis to Identify Novel Therapeutic Targets
Hanaford A, Archer T, Price A, Kahlert U, Maciaczyk J, Nikkhah G, Kim J, Ehrenberger T, Clemons P, Dančík V, Seashore-Ludlow B, Viswanathan V, Stewart M, Rees M, Shamji A, Schreiber S, Fraenkel E, Pomeroy S, Mesirov J, Tamayo P, Eberhart C, Raabe E. DiSCoVERing Innovative Therapies for Rare Tumors: Combining Genetically Accurate Disease Models with In Silico Analysis to Identify Novel Therapeutic Targets. Clinical Cancer Research 2016, 22: 3903-3914. PMID: 27012813, PMCID: PMC5055054, DOI: 10.1158/1078-0432.ccr-15-3011.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisBiomarkersCell Line, TumorCerebellar NeoplasmsComputational BiologyComputer SimulationCyclin-Dependent KinasesDisease Models, AnimalDrug DiscoveryGene Expression ProfilingGenetic Predisposition to DiseaseHumansMedulloblastomaMiceModels, BiologicalNeural Stem CellsPhosphorylationPiperazinesProto-Oncogene Proteins c-aktProto-Oncogene Proteins c-mycPyridinesTranscriptomeTumor Suppressor Protein p53Xenograft Model Antitumor AssaysConceptsGroup 3 medulloblastomaProgenitor cellsHuman neural stemCyclin-dependent kinasesRare tumorHuman neural stem cell modelNeural stemGenetically accurate modelsSurvival of miceDominant-negative p53Stem cell modelPotential effective treatmentConstitutively active AktAggressive medulloblastomaDrug sensitivity datasetsDrug sensitivity databaseNovel therapeutic targetsMedulloblastoma xenograftsAccurate disease modelsHuman stemInnovative therapiesIncreased apoptosisNeural stem cell modelIn silico analysisIn silico analysis methods
2015
A Functional Landscape of Resistance to ALK Inhibition in Lung Cancer
Wilson FH, Johannessen CM, Piccioni F, Tamayo P, Kim JW, Van Allen EM, Corsello SM, Capelletti M, Calles A, Butaney M, Sharifnia T, Gabriel SB, Mesirov JP, Hahn WC, Engelman JA, Meyerson M, Root DE, Jänne PA, Garraway LA. A Functional Landscape of Resistance to ALK Inhibition in Lung Cancer. Cancer Cell 2015, 27: 397-408. PMID: 25759024, PMCID: PMC4398996, DOI: 10.1016/j.ccell.2015.02.005.Peer-Reviewed Original ResearchConceptsFunctional genetic studiesG protein-coupled receptorsResistance driversALK inhibitionFunctional landscapeGenetic studiesLung cancer cellsALK inhibitor resistanceResistance pathwaysMechanisms of resistanceReceptor familyPKC activationPurinergic receptor familyPKC inhibitionCrizotinib-resistant ALKCancer cellsInhibitor resistanceGene signatureDependent mechanismLung cancerLung tumorsALK inhibitorsInhibitionALKMechanism
2014
A Melanoma Cell State Distinction Influences Sensitivity to MAPK Pathway Inhibitors
Konieczkowski D, Johannessen C, Abudayyeh O, Kim J, Cooper Z, Piris A, Frederick D, Barzily-Rokni M, Straussman R, Haq R, Fisher D, Mesirov J, Hahn W, Flaherty K, Wargo J, Tamayo P, Garraway L. A Melanoma Cell State Distinction Influences Sensitivity to MAPK Pathway Inhibitors. Cancer Discovery 2014, 4: 816-827. PMID: 24771846, PMCID: PMC4154497, DOI: 10.1158/2159-8290.cd-13-0424.Peer-Reviewed Original ResearchMeSH KeywordsAnilidesBenzimidazolesBenzocycloheptenesCell Line, TumorCells, CulturedDrug Resistance, NeoplasmGene Expression Regulation, NeoplasticHepatocyte Growth FactorHumansIndolesMAP Kinase Signaling SystemMelanocytesMelanomaMicrophthalmia-Associated Transcription FactorNF-kappa B p50 SubunitProtein Kinase InhibitorsProto-Oncogene Proteins B-rafProto-Oncogene Proteins c-metPyridinesQuinolinesSulfonamidesTriazolesConceptsBRAF(V600)-mutant melanomaMAPK pathway inhibitorsNF-kB activationPathway inhibitorNF-kBMelanocyte lineage transcription factor MITFCell linesDrug-sensitive cell linesResistance to MAPK pathway inhibitorsMITF expressionReceptor tyrosine kinase AXLTranscription factor MITFTyrosine kinase AXLResistance marker genesResistant cell linesNF-kB signalingResistant to inhibitionClinical benefitPatient biopsiesMEK inhibitorsTranscriptional profilesOncogenic BRAF(V600EDrug resistanceInhibitor sensitivityCell states