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
Activation of KrasG12D in Subset of Alveolar Type II Cells Enhances Cellular Plasticity in Lung Adenocarcinoma
Chaudhary P, Xu X, Wang G, Hoj J, Rampersad R, Asselin-Labat M, Ting S, Kim W, Tamayo P, Pendergast A, Onaitis M. Activation of KrasG12D in Subset of Alveolar Type II Cells Enhances Cellular Plasticity in Lung Adenocarcinoma. Cancer Research Communications 2023, 3: 2400-2411. PMID: 37882674, PMCID: PMC10668634, DOI: 10.1158/2767-9764.crc-22-0408.Peer-Reviewed Original ResearchConceptsType II cellsLung adenocarcinomaDual-positive cellsII cellsKRAS-mutant lung adenocarcinomaDevelopment of novel targeted therapeuticsTumor-initiating cellsNotch signalingAlveolar type II cellsNovel targeted therapeuticsCell of originThree-dimensional organoid culturesSOX2 upregulationKRAS activationAdenocarcinomaMouse modelTherapeutic strategiesProliferation of cellsGain-of-functionRNA sequencing analysisTransplantation studiesCellular plasticityOrganoid culturesSOX2 levelsNotch pathwayTargeting 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 trials
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
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 translationKRASMEKInnateInhibition
2017
KEAP1 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
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
KRAS 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