2023
Targeting 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
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 immunogenicity
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 ResearchMeSH KeywordsDrug Resistance, NeoplasmHumansMelanomaModels, BiologicalMutationProtein Kinase InhibitorsProto-Oncogene Proteins B-rafConceptsDrug 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 translationKRASMEKInnateInhibitionEx 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
2016
Characterizing 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-gradeA 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 statesKRAS and YAP1 Converge to Regulate EMT and Tumor Survival
Shao D, Xue W, Krall E, Bhutkar A, Piccioni F, Wang X, Schinzel A, Sood S, Rosenbluh J, Kim J, Zwang Y, Roberts T, Root D, Jacks T, Hahn W. KRAS and YAP1 Converge to Regulate EMT and Tumor Survival. Cell 2014, 158: 171-184. PMID: 24954536, PMCID: PMC4110062, DOI: 10.1016/j.cell.2014.06.004.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAnimalsCell Cycle ProteinsCell SurvivalColonic NeoplasmsDrug Delivery SystemsDrug Resistance, NeoplasmEpithelial-Mesenchymal TransitionHCT116 CellsHumansLung NeoplasmsMicePhosphoproteinsProto-Oncogene ProteinsProto-Oncogene Proteins p21(ras)Ras ProteinsSignal TransductionTranscription FactorsTranscriptional ActivationYAP-Signaling ProteinsConceptsEpithelial-mesenchymal transitionTranscriptional regulator of epithelial-mesenchymal transitionOncogenic Ras signalingColon cancer cell linesTranscriptional coactivator YAP1KRAS-dependent cellsRegulator of epithelial-mesenchymal transitionMurine lung cancer modelTranscriptional regulationCancer cell linesMutant allelesRas signalingTranscription factor FosOncogenic RasTranscriptional programsLung cancer modelRegulating epithelial-mesenchymal transitionMolecular basisOncogenic alleleCell transformationYAP1YAP1 signalingPromote survivalCancer cellsOncogenic dependency