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