2024
Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer
Robles-Oteíza C, Hastings K, Choi J, Sirois I, Ravi A, Expósito F, de Miguel F, Knight J, López-Giráldez F, Choi H, Socci N, Merghoub T, Awad M, Getz G, Gainor J, Hellmann M, Caron É, Kaech S, Politi K. Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer. Journal Of Experimental Medicine 2024, 222: e20231106. PMID: 39585348, DOI: 10.1084/jem.20231106.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsNon-small cell lung cancerAcquired resistanceCheckpoint inhibitorsResistant tumorsPatients treated with anti-PD-1/PD-L1 therapyAnti-PD-1/PD-L1 therapyLung cancerResistance to immune checkpoint inhibitorsAssociated with decreased progression-free survivalHypoxia activated pro-drugsTargeting hypoxic tumor regionsTreat non-small cell lung cancerAnti-CTLA-4Anti-PD-1Immune checkpoint inhibitionTumor metabolic featuresProgression-free survivalCell lung cancerResistant cancer cellsHypoxic tumor regionsMHC-II levelsRegions of hypoxiaKnock-outCheckpoint inhibitionOverexpression of Malat1 drives metastasis through inflammatory reprogramming of the tumor microenvironment
Martinez-Terroba E, Plasek-Hegde L, Chiotakakos I, Li V, de Miguel F, Robles-Oteiza C, Tyagi A, Politi K, Zamudio J, Dimitrova N. Overexpression of Malat1 drives metastasis through inflammatory reprogramming of the tumor microenvironment. Science Immunology 2024, 9: eadh5462. PMID: 38875320, DOI: 10.1126/sciimmunol.adh5462.Peer-Reviewed Original ResearchConceptsTumor microenvironmentLung adenocarcinomaMetastatic diseasePromoting metastatic diseaseGlobal chromatin accessibilityMetastasis-associated lung adenocarcinoma transcript 1Overexpression of MALAT1Lung adenocarcinoma transcript 1Lung adenocarcinoma metastasisCCL2 blockadeInflammatory reprogrammingEnhanced cell mobilityMacrophage depletionMechanism of actionTumor typesTumor progressionMouse modelCell mobilizationTumorLong noncoding RNAsParacrine secretionMetastasisCell linesTranscript 1MicroenvironmentPlasticity-induced repression of Irf6 underlies acquired resistance to cancer immunotherapy in pancreatic ductal adenocarcinoma
Kim I, Diamond M, Yuan S, Kemp S, Kahn B, Li Q, Lin J, Li J, Norgard R, Thomas S, Merolle M, Katsuda T, Tobias J, Baslan T, Politi K, Vonderheide R, Stanger B. Plasticity-induced repression of Irf6 underlies acquired resistance to cancer immunotherapy in pancreatic ductal adenocarcinoma. Nature Communications 2024, 15: 1532. PMID: 38378697, PMCID: PMC10879147, DOI: 10.1038/s41467-024-46048-7.Peer-Reviewed Original ResearchConceptsPancreatic ductal adenocarcinomaEpithelial-to-mesenchymal transitionResistance to immunotherapyT cell killingDuctal adenocarcinomaAcquired resistance to immunotherapyResistance to cancer immunotherapyMouse model of pancreatic ductal adenocarcinomaModel of pancreatic ductal adenocarcinomaExpression of immune checkpointsInterferon regulatory factor 6Effect of TNF-aEMT transcription factor ZEB1Antigen presentation machineryTumor immune microenvironmentCell-intrinsic defectsPro-apoptotic effectsPresentation machineryCancer immunotherapyImmune checkpointsTumor relapseImmune microenvironmentPrimary resistanceT cellsAcquired resistance
2023
Oncogenic context shapes the fitness landscape of tumor suppression
Blair L, Juan J, Sebastian L, Tran V, Nie W, Wall G, Gerceker M, Lai I, Apilado E, Grenot G, Amar D, Foggetti G, Do Carmo M, Ugur Z, Deng D, Chenchik A, Paz Zafra M, Dow L, Politi K, MacQuitty J, Petrov D, Winslow M, Rosen M, Winters I. Oncogenic context shapes the fitness landscape of tumor suppression. Nature Communications 2023, 14: 6422. PMID: 37828026, PMCID: PMC10570323, DOI: 10.1038/s41467-023-42156-y.Peer-Reviewed Original ResearchMammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer
de Miguel F, Gentile C, Feng W, Silva S, Sankar A, Exposito F, Cai W, Melnick M, Robles-Oteiza C, Hinkley M, Tsai J, Hartley A, Wei J, Wurtz A, Li F, Toki M, Rimm D, Homer R, Wilen C, Xiao A, Qi J, Yan Q, Nguyen D, Jänne P, Kadoch C, Politi K. Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer. Cancer Cell 2023, 41: 1516-1534.e9. PMID: 37541244, PMCID: PMC10957226, DOI: 10.1016/j.ccell.2023.07.005.Peer-Reviewed Original ResearchConceptsMammalian SWI/SNF chromatinSWI/SNF chromatinMSWI/SNF complexesGenome-wide localizationGene regulatory signaturesNon-genetic mechanismsEpithelial cell differentiationEGFR-mutant cellsChromatin accessibilitySNF complexCellular programsRegulatory signaturesTKI-resistant lung cancerGene targetsKinase inhibitor resistanceCell differentiationMesenchymal transitionTKI resistancePharmacologic disruptionTyrosine kinase inhibitor resistanceCell proliferationChromatinInhibitor resistanceEGFR-mutant lungKinase inhibitorsThe New NCI Precision Medicine Trials
Harris L, Blanke C, Erba H, Ford J, Gray R, LeBlanc M, Hu-Lieskovan S, Litzow M, Luger S, Meric-Bernstam F, O'Dwyer P, Othus M, Politi K, Shepherd L, Allegra C, Chen H, Ivy S, Korde L, Little R, McShane L, Moscow J, Patton D, Thurin M, Yee L, Doroshow J. The New NCI Precision Medicine Trials. Clinical Cancer Research 2023, 29: of1-of5. PMID: 37531248, PMCID: PMC10690084, DOI: 10.1158/1078-0432.ccr-23-0917.Peer-Reviewed Original ResearchAutologous humanized PDX modeling for immuno-oncology recapitulates features of the human tumor microenvironment
Chiorazzi M, Martinek J, Krasnick B, Zheng Y, Robbins K, Qu R, Kaufmann G, Skidmore Z, Juric M, Henze L, Brösecke F, Adonyi A, Zhao J, Shan L, Sefik E, Mudd J, Bi Y, Goedegebuure S, Griffith M, Griffith O, Oyedeji A, Fertuzinhos S, Garcia-Milian R, Boffa D, Detterbeck F, Dhanasopon A, Blasberg J, Judson B, Gettinger S, Politi K, Kluger Y, Palucka K, Fields R, Flavell R. Autologous humanized PDX modeling for immuno-oncology recapitulates features of the human tumor microenvironment. Journal For ImmunoTherapy Of Cancer 2023, 11: e006921. PMID: 37487666, PMCID: PMC10373695, DOI: 10.1136/jitc-2023-006921.Peer-Reviewed Original ResearchConceptsHuman tumor microenvironmentTumor microenvironmentTumor-immune interactionsSolid tumorsAdaptive immune activationAdaptive immune populationsIndividual tumor microenvironmentsPatient's hematopoietic systemPatient-derived xenograft tissuesVascular endothelial growth factorBone marrow hematopoietic stemBone marrow aspiratePreclinical drug testingEndothelial growth factorHematopoietic systemAutologous tumorPDX modelingPDX miceImmune activationImmune populationsMarrow aspiratesAutologous systemIndividual patientsLittermate controlsPreclinical predictionsPTEN Loss Confers Resistance to Anti-PD-1 Therapy in Non-Small Cell Lung Cancer by Increasing Tumor Infiltration of Regulatory T Cells.
Exposito F, Redrado M, Houry M, Hastings K, Molero-Abraham M, Lozano T, Solorzano J, Sanz-Ortega J, Adradas V, Amat R, Redin E, Leon S, Legarra N, Garcia J, Serrano D, Valencia K, Robles-Oteiza C, Foggetti G, Otegui N, Felip E, Lasarte J, Paz-Ares L, Zugazagoitia J, Politi K, Montuenga L, Calvo A. PTEN Loss Confers Resistance to Anti-PD-1 Therapy in Non-Small Cell Lung Cancer by Increasing Tumor Infiltration of Regulatory T Cells. Cancer Research 2023, 83: 2513-2526. PMID: 37311042, DOI: 10.1158/0008-5472.can-22-3023.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerLung squamous carcinomaAnti-PD-1 therapyRegulatory T cellsCell lung cancerImmunosuppressive microenvironmentLung cancerImmunotherapy resistanceT cellsWorse progression-free survivalCell death protein 1PTEN lossAnti-TGFβ antibodyConversion of CD4PI3K/AKT/mTOR pathwayProgression-free survivalDeath protein 1Treatment of miceImmunosuppressive tumor microenvironmentPTEN/PI3K/AKT/mTOR pathwayAKT/mTOR pathwayPD-L1TLR agonistsTumor rejectionSquamous carcinomaEfficacy of Osimertinib in Patients with Lung Cancer Positive for Uncommon EGFR Exon 19 Deletion Mutations
Grant M, Aredo J, Starrett J, Stockhammer P, van Rosenburgh I, Wurtz A, Piper-Valillo A, Piotrowska Z, Falcon C, Yu H, Aggarwal C, Scholes D, Patil T, Nguyen C, Phadke M, Li F, Neal J, Lemmon M, Walther Z, Politi K, Goldberg S. Efficacy of Osimertinib in Patients with Lung Cancer Positive for Uncommon EGFR Exon 19 Deletion Mutations. Clinical Cancer Research 2023, 29: of1-of8. PMID: 36913537, PMCID: PMC10493186, DOI: 10.1158/1078-0432.ccr-22-3497.Peer-Reviewed Original ResearchConceptsProgression-free survivalNon-small cell lung cancerInferior progression-free survivalMulticenter retrospective cohortEfficacy of osimertinibMulti-institutional cohortCell lung cancerExon 19 deletion mutationUncommon EGFRRetrospective cohortClinical outcomesClinical efficacyLung cancerOsimertinib efficacyEGFR mutationsPreclinical modelsEx19delPatientsAACR Genie databaseLater linesOsimertinibMutant cohortFirst lineCohortEfficacy
2022
Brain metastatic outgrowth and osimertinib resistance are potentiated by RhoA in EGFR-mutant lung cancer
Adua S, Arnal-Estapé A, Zhao M, Qi B, Liu Z, Kravitz C, Hulme H, Strittmatter N, López-Giráldez F, Chande S, Albert A, Melnick M, Hu B, Politi K, Chiang V, Colclough N, Goodwin R, Cross D, Smith P, Nguyen D. Brain metastatic outgrowth and osimertinib resistance are potentiated by RhoA in EGFR-mutant lung cancer. Nature Communications 2022, 13: 7690. PMID: 36509758, PMCID: PMC9744876, DOI: 10.1038/s41467-022-34889-z.Peer-Reviewed Original ResearchConceptsGene expression programsRas homolog family member ACancer cellsFamily member AEpidermal growth factor receptorExpression programsMetastatic cancer cellsSRF signalingGrowth factor receptorTumor microenvironmentLung cancerFunctional linkExtracellular lamininDrug-resistant cancer cellsMutant non-small cell lung cancerNon-small cell lung cancerCentral nervous system relapseMolecular studiesMember AEGFR-mutant lung cancerFactor receptorNervous system relapseCell lung cancerDisseminated tumor cellsBrain tumor microenvironmentBiochemical and structural basis for differential inhibitor sensitivity of EGFR with distinct exon 19 mutations
van Alderwerelt van Rosenburgh I, Lu D, Grant M, Stayrook S, Phadke M, Walther Z, Goldberg S, Politi K, Lemmon M, Ashtekar K, Tsutsui Y. Biochemical and structural basis for differential inhibitor sensitivity of EGFR with distinct exon 19 mutations. Nature Communications 2022, 13: 6791. PMID: 36357385, PMCID: PMC9649653, DOI: 10.1038/s41467-022-34398-z.Peer-Reviewed Original Research
2018
The Impact of Smoking and TP53 Mutations in Lung Adenocarcinoma Patients with Targetable Mutations—The Lung Cancer Mutation Consortium (LCMC2)
Aisner DL, investigators F, Sholl L, Berry L, Rossi M, Chen H, Fujimoto J, Moreira A, Ramalingam S, Villaruz L, Otterson G, Haura E, Politi K, Glisson B, Cetnar J, Garon E, Schiller J, Waqar S, Sequist L, Brahmer J, Shyr Y, Kugler K, Wistuba I, Johnson B, Minna J, Kris M, Bunn P, Kwiatkowski D. The Impact of Smoking and TP53 Mutations in Lung Adenocarcinoma Patients with Targetable Mutations—The Lung Cancer Mutation Consortium (LCMC2). Clinical Cancer Research 2018, 24: 1038-1047. PMID: 29217530, PMCID: PMC7008001, DOI: 10.1158/1078-0432.ccr-17-2289.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinoma of LungAdultAgedAged, 80 and overAntineoplastic AgentsBiomarkers, TumorCarcinogenesisDNA Mutational AnalysisFemaleHigh-Throughput Nucleotide SequencingHumansLung NeoplasmsMaleMiddle AgedMolecular Targeted TherapyMutationPrognosisProspective StudiesSmokingSurvival AnalysisTreatment OutcomeTumor Suppressor Protein p53Young AdultConceptsLung Cancer Mutation ConsortiumLung adenocarcinomaPrior smoking historyTargetable driver alterationsSimilar survival benefitAdvanced lung adenocarcinomaHistory of smokingOncogenic driver mutationsEfficacy of treatmentClin Cancer ResClinical characteristicsSmoking historySurvival benefitShorter survivalTargetable driversLung cancerPredictive markerLonger survivalOncogenic driver eventsTargeted therapyTherapy selectionCancer-related genesPatientsDriver alterationsMolecular testing
2012
Targeting the FOXO1/KLF6 axis regulates EGFR signaling and treatment response
Sangodkar J, Dhawan N, Melville H, Singh V, Yuan E, Rana H, Izadmehr S, Farrington C, Mazhar S, Katz S, Albano T, Arnovitz P, Okrent R, Ohlmeyer M, Galsky M, Burstein D, Zhang D, Politi K, DiFeo A, Narla G. Targeting the FOXO1/KLF6 axis regulates EGFR signaling and treatment response. Journal Of Clinical Investigation 2012, 122: 2637-2651. PMID: 22653055, PMCID: PMC3386822, DOI: 10.1172/jci62058.Peer-Reviewed Original ResearchMeSH KeywordsActive Transport, Cell NucleusAdenocarcinomaAdenocarcinoma of LungAnimalsAntineoplastic AgentsCell Line, TumorDrug Resistance, NeoplasmDrug SynergismEnzyme ActivationErbB ReceptorsErlotinib HydrochlorideFemaleForkhead Box Protein O1Forkhead Transcription FactorsGene Expression Regulation, NeoplasticHumansKruppel-Like Factor 6Kruppel-Like Transcription FactorsLung NeoplasmsMiceMice, Inbred BALB CMice, NudeMutationProto-Oncogene ProteinsProto-Oncogene Proteins c-aktQuinazolinesReal-Time Polymerase Chain ReactionSignal TransductionTranscription, GeneticTrifluoperazineTumor BurdenXenograft Model Antitumor AssaysConceptsAnti-EGFR-based therapyEGFR signalingKruppel-like factor 6Lung adenocarcinomaForkhead box O1Xenograft models of lung adenocarcinomaModel of lung adenocarcinomaMetastatic lung adenocarcinomaTreat advanced cancersMolecular drivers of disease progressionDrivers of disease progressionOncogenic EGFR signalingActivation of Akt signalingFoxO1 nuclear exportTreating resistant diseaseIn vivo modelsCell culturesErlotinib resistanceResistant diseaseTreatment responseMolecular therapiesXenograft modelFDA-approved drugsDisease progressionEGFR activation
2005
Oncogenes Come of Age
VARMUS H, PAO W, POLITI K, PODSYPANINA K, DU Y. Oncogenes Come of Age. Cold Spring Harbor Symposia On Quantitative Biology 2005, 70: 1-9. PMID: 16869733, PMCID: PMC1791364, DOI: 10.1101/sqb.2005.70.039.Chapters