2024
Targeting DHX9 triggers tumor-intrinsic interferon response and replication stress in Small Cell Lung Cancer
Murayama T, Nakayama J, Jiang X, Miyata K, Morris A, Cai K, Prasad R, Ma X, Efimov A, Belani N, Gerstein E, Tan Y, Zhou Y, Kim W, Maruyama R, Campbell K, Chen L, Yang Y, Balachandran S, Canadas I. Targeting DHX9 triggers tumor-intrinsic interferon response and replication stress in Small Cell Lung Cancer. Cancer Discovery 2024, 14: 468-491. PMID: 38189443, PMCID: PMC10905673, DOI: 10.1158/2159-8290.cd-23-0486.Peer-Reviewed Original ResearchConceptsSmall cell lung cancerDExD/H-box helicase 9Cell lung cancerCold tumorsLung cancerResponse to immune-checkpoint blockadeInnate immunityEnhance immunotherapy efficacyImmune-checkpoint blockadeImmunogenic tumor microenvironmentImmunologically cold tumorsNucleic acid-sensing pathwaysActivate innate immunityAntitumor immunityImmunotherapy efficacyReplication stressTumor microenvironmentTumor growthViral mimicryTumorImmune responseCancer cellsInterferon responseCytoplasmic dsRNACancer
2023
Targeting the RET tyrosine kinase in neuroblastoma: A review and application of a novel selective drug design strategy
Steen E, Basilaia M, Kim W, Getz T, Gustafson J, Zage P. Targeting the RET tyrosine kinase in neuroblastoma: A review and application of a novel selective drug design strategy. Biochemical Pharmacology 2023, 216: 115751. PMID: 37595672, PMCID: PMC10911250, DOI: 10.1016/j.bcp.2023.115751.Peer-Reviewed Original ResearchConceptsRET inhibitorsRET inhibitionSolid tumorsIncreased RET expressionAssociated with poor prognosisPediatric solid tumorsNeuroblastoma tumor cellsPapillary thyroid cancerTyrosine kinaseOncogenic RET mutationsRET tyrosine kinaseProgression of multiple typesTransmembrane receptor tyrosine kinaseRET mutationsRET expressionReceptor tyrosine kinasesThyroid cancerNeuroblastoma tumorsPoor prognosisPreclinical studiesTumor cellsBreast cancerKinase inhibitorsLung adenocarcinomaClinical trialsTargeting TBK1 to overcome resistance to cancer immunotherapy
Sun Y, Revach O, Anderson S, Kessler E, Wolfe C, Jenney A, Mills C, Robitschek E, Davis T, Kim S, Fu A, Ma X, Gwee J, Tiwari P, Du P, Sindurakar P, Tian J, Mehta A, Schneider A, Yizhak K, Sade-Feldman M, LaSalle T, Sharova T, Xie H, Liu S, Michaud W, Saad-Beretta R, Yates K, Iracheta-Vellve A, Spetz J, Qin X, Sarosiek K, Zhang G, Kim J, Su M, Cicerchia A, Rasmussen M, Klempner S, Juric D, Pai S, Miller D, Giobbie-Hurder A, Chen J, Pelka K, Frederick D, Stinson S, Ivanova E, Aref A, Paweletz C, Barbie D, Sen D, Fisher D, Corcoran R, Hacohen N, Sorger P, Flaherty K, Boland G, Manguso R, Jenkins R. Targeting TBK1 to overcome resistance to cancer immunotherapy. Nature 2023, 615: 158-167. PMID: 36634707, PMCID: PMC10171827, DOI: 10.1038/s41586-023-05704-6.Peer-Reviewed Original ResearchConceptsOvercome resistance to cancer immunotherapyResistance to cancer immunotherapyPD-1 blockadeCancer immunotherapyImmune-evasion genesResponse to PD-1 blockadePatient-derived tumor modelsPatient-derived organoidsEffective treatment strategiesTBK1 inhibitionPD-1Effector cytokinesConcordant findingsTumor cellsTumor modelCaspase-dependent cell deathResponse to TNFTreatment strategiesTargeting TBK1ImmunotherapyPharmacological toolsBlockadeTumor spheroidsCell deathTBK1
2022
CHMP2A 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
2021
An expanded universe of cancer targets
Hahn W, Bader J, Braun T, Califano A, Clemons P, Druker B, Ewald A, Fu H, Jagu S, Kemp C, Kim W, Kuo C, McManus M, B. Mills G, Mo X, Sahni N, Schreiber S, Talamas J, Tamayo P, Tyner J, Wagner B, Weiss W, Gerhard D, Dancik V, Gill S, Hua B, Sharifnia T, Viswanathan V, Zou Y, Dela Cruz F, Kung A, Stockwell B, Boehm J, Dempster J, Manguso R, Vazquez F, Cooper L, Du Y, Ivanov A, Lonial S, Moreno C, Niu Q, Owonikoko T, Ramalingam S, Reyna M, Zhou W, Grandori C, Shmulevich I, Swisher E, Cai J, Chan I, Dunworth M, Ge Y, Georgess D, Grasset E, Henriet E, Knútsdóttir H, Lerner M, Padmanaban V, Perrone M, Suhail Y, Tsehay Y, Warrier M, Morrow Q, Nechiporuk T, Long N, Saultz J, Kaempf A, Minnier J, Tognon C, Kurtz S, Agarwal A, Brown J, Watanabe-Smith K, Vu T, Jacob T, Yan Y, Robinson B, Lind E, Kosaka Y, Demir E, Estabrook J, Grzadkowski M, Nikolova O, Chen K, Deneen B, Liang H, Bassik M, Bhattacharya A, Brennan K, Curtis C, Gevaert O, Ji H, Karlsson K, Karagyozova K, Lo Y, Liu K, Nakano M, Sathe A, Smith A, Spees K, Wong W, Yuki K, Hangauer M, Kaufman D, Balmain A, Bollam S, Chen W, Fan Q, Kersten K, Krummel M, Li Y, Menard M, Nasholm N, Schmidt C, Serwas N, Yoda H, Ashworth A, Bandyopadhyay S, Bivona T, Eades G, Oberlin S, Tay N, Wang Y, Weissman J. An expanded universe of cancer targets. Cell 2021, 184: 1142-1155. PMID: 33667368, PMCID: PMC8066437, DOI: 10.1016/j.cell.2021.02.020.Peer-Reviewed Original ResearchConceptsNon-oncogene dependenciesDiversity of therapeutic targetsSomatically altered genesCancer targetCancer allelesInfluence therapyCancer genomesGenomic characterizationTherapeutic strategiesAltered genesCancer featuresCancer genesClinical translationCancerCancer biologyTherapeutic targetTumorGenomeGenes
2020
WNT Signaling Driven by R-spondin 1 and LGR6 in High-grade Serous Ovarian Cancer
LEE S, JUN J, KIM W, TAMAYO P, HOWELL S. WNT Signaling Driven by R-spondin 1 and LGR6 in High-grade Serous Ovarian Cancer. Anticancer Research 2020, 40: 6017-6028. PMID: 33109540, PMCID: PMC9312105, DOI: 10.21873/anticanres.14623.Peer-Reviewed Original ResearchConceptsHigh-grade serous ovarian cancerGene set enrichment analysisSerous ovarian cancerWnt signalingOvarian surfaceExpression of RSPO1Gene set enrichment analysis methodRNA-seq dataControl cell fateR-spondinOvarian cancerAnalysis of genesNormal tissuesWnt signaling pathwayHuman Protein AtlasAdjacent genesImpact overall survivalLevel of expressionRNA-seqAssociation studiesCell fateCopy numberGO pathwaysAnalysis of TCGAEnrichment analysisMesenchymal 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 immortalityCannabinoids Promote Progression of HPV-Positive Head and Neck Squamous Cell Carcinoma via p38 MAPK Activation
Liu C, Sadat S, Ebisumoto K, Sakai A, Panuganti B, Ren S, Goto Y, Haft S, Fukusumi T, Ando M, Saito Y, Guo T, Tamayo P, Yeerna H, Kim W, Hubbard J, Sharabi A, Gutkind J, Califano J. Cannabinoids Promote Progression of HPV-Positive Head and Neck Squamous Cell Carcinoma via p38 MAPK Activation. Clinical Cancer Research 2020, 26: 2693-2703. PMID: 31932491, PMCID: PMC7538010, DOI: 10.1158/1078-0432.ccr-18-3301.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisCannabinoidsCell MovementCell ProliferationFemaleHead and Neck NeoplasmsHumansMiceMice, NudeP38 Mitogen-Activated Protein KinasesPapillomaviridaePapillomavirus InfectionsPrognosisReceptors, CannabinoidSquamous Cell Carcinoma of Head and NeckTumor Cells, CulturedXenograft Model Antitumor AssaysConceptsHead and neck squamous cell carcinomaHPV-positive head and neck squamous cell carcinomaHPV-positive HNSCC cell linesNeck squamous cell carcinomaHNSCC cell linesSingle-sample gene set enrichment analysisSquamous cell carcinomaP38 MAPK pathway activationHNSCC cohortCell carcinomaMAPK pathway activationHPV-negative head and neck squamous cell carcinomaHuman papillomavirus (HPV)-related headCell linesAnimal modelsCannabinoid receptor activationHPV- HNSCC patientsHead and neck squamous cell carcinomas dataMarijuana usePathway activationDaily marijuana useWhole-genome expression analysisCannabinoid exposureHNSCC patientsP38 MAPK activationSTRIPAK directs PP2A activity toward MAP4K4 to promote oncogenic transformation of human cells
Kim J, Berrios C, Kim M, Schade A, Adelmant G, Yeerna H, Damato E, Iniguez A, Florens L, Washburn M, Stegmaier K, Gray N, Tamayo P, Gjoerup O, Marto J, DeCaprio J, Hahn W. STRIPAK directs PP2A activity toward MAP4K4 to promote oncogenic transformation of human cells. ELife 2020, 9: e53003. PMID: 31913126, PMCID: PMC6984821, DOI: 10.7554/elife.53003.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAnimalsCalmodulin-Binding ProteinsCell ProliferationCell Transformation, NeoplasticFemaleGene Knockdown TechniquesHEK293 CellsHeterograftsHumansIntracellular Signaling Peptides and ProteinsMicePhosphoprotein PhosphatasesProtein Serine-Threonine KinasesSignal TransductionTranscription FactorsYAP-Signaling ProteinsConceptsStriatin-interacting phosphatase and kinaseSV40 small t antigenB subunitCell transformationPP2A subunitsHippo pathway effector YAP1Regulatory B subunitPP2A B subunitsPP2A-mediated dephosphorylationSmall t antigenInduce cell transformationPP2A functionPP2A complexPP2A activityOncogenic transformationSubunit interactionsPP2AHuman cancersT antigenMAP4K4SubunitAssociated with STCell alterationsPartial lossCells
2019
Modelling bistable tumour population dynamics to design effective treatment strategies
Akhmetzhanov A, Kim J, Sullivan R, Beckman R, Tamayo P, Yeang C. Modelling bistable tumour population dynamics to design effective treatment strategies. Journal Of Theoretical Biology 2019, 474: 88-102. PMID: 31077681, PMCID: PMC9534689, DOI: 10.1016/j.jtbi.2019.05.005.Peer-Reviewed Original ResearchConceptsDrug resistanceHeterogeneous tumorsTumor cellsTreatment strategiesDevelopment of optimal therapeutic strategiesEffects of targeted drugsBRAF-mutant melanomaProcess of tumor growthOptimal therapeutic strategyDrug resistance characteristicsHeterogeneous tumor cellsReverse drug resistanceActivated alternative pathwayEmergence of resistanceCancer treatment modalityEffective treatment strategiesDesigning effective treatment strategiesDrug holidayBRAF inhibitorsPeriodate treatmentDrug regimensTreatment modalitiesGenetic alterationsTumor growthDrug sensitivity
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 methodsCharacterizing genomic alterations in cancer by complementary functional associations
Kim J, Botvinnik O, Abudayyeh O, Birger C, Rosenbluh J, Shrestha Y, Abazeed M, Hammerman P, DiCara D, Konieczkowski D, Johannessen C, Liberzon A, Alizad-Rahvar A, Alexe G, Aguirre A, Ghandi M, Greulich H, Vazquez F, Weir B, Van Allen E, Tsherniak A, Shao D, Zack T, Noble M, Getz G, Beroukhim R, Garraway L, Ardakani M, Romualdi C, Sales G, Barbie D, Boehm J, Hahn W, Mesirov J, Tamayo P. Characterizing genomic alterations in cancer by complementary functional associations. Nature Biotechnology 2016, 34: 539-546. PMID: 27088724, PMCID: PMC4868596, DOI: 10.1038/nbt.3527.Peer-Reviewed Original Research
2015
KRAS Genomic Status Predicts the Sensitivity of Ovarian Cancer Cells to Decitabine
Stewart M, Tamayo P, Wilson A, Wang S, Chang Y, Kim J, Khabele D, Shamji A, Schreiber S. KRAS Genomic Status Predicts the Sensitivity of Ovarian Cancer Cells to Decitabine. Cancer Research 2015, 75: 2897-2906. PMID: 25968887, PMCID: PMC4506246, DOI: 10.1158/0008-5472.can-14-2860.Peer-Reviewed Original ResearchConceptsOvarian cancer cellsCancer cellsOvarian cancerHigh-grade serous ovarian cancer cellsGenomic statusBiomarkers of drug responseBcl-2 family inhibitorsAntitumor response rateSerous ovarian cancer cellsTreated with decitabineInhibit DNA methylationBreast cancer cellsDownregulation of DNMT1DNA methyltransferase inhibitionKRAS statusDNA methylationPredictive biomarkersSolid tumorsMEK inhibitorsMEK/ERK phosphorylationDecitabineBcl-2Drug responseXenograft modelLow-grade