2025
Use of baseline plasma circulating tumor DNA (ctDNA) to predict duration of endocrine therapy (ET) and CDK4/6 inhibitor (CDK4/6i) therapy (tx) and to analyze intrinsic vs acquired endocrine resistance.
De Placido P, Hughes M, Weipert C, Sammons S, Morganti S, Parsons H, Abravanel D, Giordano A, Smith K, Patel A, Kirkner G, Stever C, Suggs G, Sendrick K, Snow C, Winer E, Tolaney S, Lin N, Jeselsohn R. Use of baseline plasma circulating tumor DNA (ctDNA) to predict duration of endocrine therapy (ET) and CDK4/6 inhibitor (CDK4/6i) therapy (tx) and to analyze intrinsic vs acquired endocrine resistance. Journal Of Clinical Oncology 2025, 43: 1075-1075. DOI: 10.1200/jco.2025.43.16_suppl.1075.Peer-Reviewed Original ResearchMetastatic breast cancerCirculating tumor DNACopy number lossHR+/HER2- metastatic breast cancerAcquired ResistanceEndocrine therapyLiver metastasesGenomic profilingCDKN2A copy number lossHormone receptor-positive/HER2-negativePlasma circulating tumor DNADuration of endocrine therapyPresence of liver metastasesIntrinsic resistanceCompare genomic profilesBaseline TFPlasma samplesAcquired endocrine resistanceMetastatic breast cancer diagnosisStandard-of-careCox regression modelsESR1 fusionsTumor sheddingSecond-lineMedian duration
2024
Mechanisms of immunotherapy resistance in small cell lung cancer
Nie Y, Schalper K, Chiang A. Mechanisms of immunotherapy resistance in small cell lung cancer. Cancer Drug Resistance 2024, 7: n/a-n/a. PMID: 39802951, PMCID: PMC11724353, DOI: 10.20517/cdr.2024.154.Peer-Reviewed Original ResearchSmall-cell lung cancerImmune checkpoint inhibitorsSociety for Immunotherapy of CancerImmunotherapy resistanceTumor microenvironmentPrimary resistanceAcquired ResistancePrimary resistance to immune checkpoint inhibitorsLung cancerResistance to immune checkpoint inhibitorsMechanisms of immunotherapy resistanceSmall cell lung cancerImmunosuppressive immune cellsImmunotherapy to chemotherapyResistance to immunotherapySociety for ImmunotherapyImmunotherapy of cancerAggressive neuroendocrine tumorCell lung cancerCheckpoint inhibitorsTumor immunogenicityEffective immunotherapyNeuroendocrine tumorsPoor prognosisAntigen presentationHypoxia 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, PMCID: PMC11602551, 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 inhibitionPlasticity-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
cfDNA NGS for Identification of Primary and Acquired Resistance in Patients With Lung Cancer and EGFR Mutations
Peleg A, Del Re M, Raphael A, Wang X, Berkovich A, Tsuriel S, Lichtman S, Elias E, Gomez J, Doroshow D, Smith C, Veluswamy R, Marron T, Rohs N, Mack P, Hirsch F, Rolfo C. cfDNA NGS for Identification of Primary and Acquired Resistance in Patients With Lung Cancer and EGFR Mutations. The Journal Of Liquid Biopsy 2023, 1: 100047. DOI: 10.1016/j.jlb.2023.100047.Peer-Reviewed Original Research
2022
Downregulation of MEIS1 mediated by ELFN1-AS1/EZH2/DNMT3a axis promotes tumorigenesis and oxaliplatin resistance in colorectal cancer
Li Y, Gan Y, Liu J, Li J, Zhou Z, Tian R, Sun R, Liu J, Xiao Q, Li Y, Lu P, Peng Y, Peng Y, Shu G, Yin G. Downregulation of MEIS1 mediated by ELFN1-AS1/EZH2/DNMT3a axis promotes tumorigenesis and oxaliplatin resistance in colorectal cancer. Signal Transduction And Targeted Therapy 2022, 7: 87. PMID: 35351858, PMCID: PMC8964798, DOI: 10.1038/s41392-022-00902-6.Peer-Reviewed Original ResearchConceptsOxaliplatin resistanceColorectal cancerTumor growthMEIS1 expressionCell sensitivity to oxaliplatinPreventing DNA damage repairCombination of oxaliplatinSurvival of CRC patientsTreatment of colorectal cancerSensitivity to oxaliplatinEZH2 inhibitor GSK126Suppressed tumor growthReverse oxaliplatin resistanceFrontline treatmentAcquired ResistanceCRC patientsInhibitor GSK126OxaliplatinFEN1 expressionTherapeutic strategiesDNA damage repairELFN1-AS1Cell survivalMeis1Patients
2021
Immune Therapy: What Can We Learn From Acquired Resistance?
Grant M, Politi K, Gettinger S. Immune Therapy: What Can We Learn From Acquired Resistance? Current Cancer Research 2021, 75-114. DOI: 10.1007/978-3-030-74028-3_5.ChaptersNon-small cell lung cancerAdvanced non-small cell lung cancerDeath-1 pathway inhibitorsPD-1 axis inhibitorsInitial tumor regressionCell lung cancerImmune checkpoint pathwaysIFN-γ signalingMediators of resistanceDisease stabilitySystemic progressionMost patientsLocal therapyClinical criteriaLung cancerTumor regressionTumor typesDisease sitesPathway inhibitorAcquired ResistancePresentation defectPatientsTranslational workProgressionEpigenetic changesClinical definition of acquired resistance to immunotherapy in patients with metastatic non-small-cell lung cancer
Schoenfeld A, Antonia S, Awad M, Felip E, Gainor J, Gettinger S, Hodi F, Johnson M, Leighl N, Lovly C, Mok T, Perol M, Reck M, Solomon B, Soria J, Tan D, Peters S, Hellmann M. Clinical definition of acquired resistance to immunotherapy in patients with metastatic non-small-cell lung cancer. Annals Of Oncology 2021, 32: 1597-1607. PMID: 34487855, PMCID: PMC12013006, DOI: 10.1016/j.annonc.2021.08.2151.Peer-Reviewed Original ResearchConceptsCell lung cancerClinical definitionAcquired ResistanceLung cancerClinical trialsCell death protein 1/Death protein 1/Consistent clinical definitionPersistent antitumor immunityProspective clinical trialsInvestigational immunotherapiesAntitumor immunityObjective responseProgressive diseaseAntibody treatmentNSCLC biologyInitial respondersTreatment strategiesClinical reportsPatientsBlockadeImmunotherapyTherapeutic discoveryCancerUniform criteria
2020
Repeat tick exposure elicits distinct immune responses in guinea pigs and mice
Kurokawa C, Narasimhan S, Vidyarthi A, Booth CJ, Mehta S, Meister L, Diktas H, Strank N, Lynn GE, DePonte K, Craft J, Fikrig E. Repeat tick exposure elicits distinct immune responses in guinea pigs and mice. Ticks And Tick-borne Diseases 2020, 11: 101529. PMID: 32993942, PMCID: PMC7530331, DOI: 10.1016/j.ttbdis.2020.101529.Peer-Reviewed Original ResearchConceptsGuinea pigsElicit distinct immune responsesDistinct immune responsesGuinea pig modelLocal blood flowImmune animalsInflammatory pathwaysTick rejectionMechanisms of resistanceImmune responseMouse modelVaccine candidatesBite siteBlood flowPig modelCoagulation pathwayComplement activationAcquired ResistanceProtective antigenTick detachmentTick proteinsBlood mealMiceTick infestationRNA sequencingThe Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor–Positive Metastatic Breast Cancer
Wander SA, Cohen O, Gong X, Johnson GN, Buendia-Buendia JE, Lloyd MR, Kim D, Luo F, Mao P, Helvie K, Kowalski KJ, Nayar U, Waks AG, Parsons SH, Martinez R, Litchfield LM, Ye XS, Yu C, Jansen VM, Stille JR, Smith PS, Oakley GJ, Chu QS, Batist G, Hughes ME, Kremer JD, Garraway LA, Winer EP, Tolaney SM, Lin NU, Buchanan SG, Wagle N. The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor–Positive Metastatic Breast Cancer. Cancer Discovery 2020, 10: 1174-1193. PMID: 32404308, PMCID: PMC8815415, DOI: 10.1158/2159-8290.cd-19-1390.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic AgentsBiopsyBreast NeoplasmsCell Cycle ProteinsCell Line, TumorCheckpoint Kinase 1Drug Resistance, NeoplasmExome SequencingFemaleGenomicsHumansProtein Kinase InhibitorsProto-Oncogene Proteins c-aktProto-Oncogene Proteins p21(ras)Receptors, SteroidRetinoblastoma Binding ProteinsUbiquitin-Protein LigasesConceptsCyclin-dependent kinase 4/6 inhibitorsMetastatic breast cancerBreast cancerResistant tumorsHormone receptor-positive metastatic breast cancerHormone receptor-positive breast cancerReceptor-positive breast cancerEstrogen receptor expressionCandidate resistance mechanismsWhole-exome sequencingPrecision-based approachesCDK4/6i resistanceMechanisms of resistanceReceptor expressionTherapeutic strategiesCDK4/6iTherapeutic opportunitiesPatient samplesTumorsIssue featurePatientsCancerAcquired ResistanceCancer cellsAlterationsAcquired Resistance to HER2-Targeted Therapies Creates Vulnerability to ATP Synthase Inhibition
Gale M, Li Y, Cao J, Liu ZZ, Holmbeck MA, Zhang M, Lang SM, Wu L, Do Carmo M, Gupta S, Aoshima K, DiGiovanna MP, Stern DF, Rimm DL, Shadel GS, Chen X, Yan Q. Acquired Resistance to HER2-Targeted Therapies Creates Vulnerability to ATP Synthase Inhibition. Cancer Research 2020, 80: 524-535. PMID: 31690671, PMCID: PMC7002225, DOI: 10.1158/0008-5472.can-18-3985.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic Combined Chemotherapy ProtocolsApoptosisBreast NeoplasmsCell ProliferationDrug Resistance, NeoplasmEnzyme InhibitorsFemaleHumansMiceMice, Inbred NODMice, SCIDMitochondrial Proton-Translocating ATPasesOligomycinsReceptor, ErbB-2TrastuzumabTumor Cells, CulturedXenograft Model Antitumor AssaysConceptsResistant cellsHER2-Targeted TherapyTrastuzumab-resistant tumorsNew therapeutic strategiesNovel potential targetDrug-free mediumAntibody therapySynthase inhibitionLow doseTherapeutic strategiesTrastuzumabBreast tumorsHER2TherapyAcquired ResistanceTumorsPotential targetMitochondrial respirationCellsSelective dependencyInhibitionMinimal changesNovel vulnerabilitiesATP synthase inhibitionOligomycin A
2015
Abstract PR04: A melanoma transcriptional state distinction influences sensitivity to MAPK pathway inhibitors
Johannessen C, Konieczkowski D, 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. Abstract PR04: A melanoma transcriptional state distinction influences sensitivity to MAPK pathway inhibitors. Clinical Cancer Research 2015, 21: pr04-pr04. DOI: 10.1158/1557-3265.pms14-pr04.Peer-Reviewed Original ResearchBRAFV600-mutant melanomaMAPK pathway inhibitorsPathway inhibitorCell linesMelanocyte lineage transcription factor MITFPanel of melanoma cell linesResistance to MAPK pathway inhibitorsMAPK pathway inhibitionReceptor tyrosine kinase AXLDrug-resistant cell linesImprove cancer therapyTyrosine kinase AXLMelanoma cell linesSensitive cell linesNF-kB activationNF-kB signalingRAF/MEK inhibitionMelanoma patientsClinical responseTranscription factor MITFMalignant melanomaDrug susceptibilityAcquired ResistancePatient biopsiesMEK inhibitors
2014
Continued Afatinib (A) With the Addition of Cetuximab (C) After Progression on Afatinib in Patients With Acquired Resistance (AR) to Gefitinib (G) or Erlotinib (E) Metastatic Non-Small Cell Lung Cancer
Horn L, Gettinger S, Camidge R, Smit E, Janjigian Y, Pao W, Schnell D, Wang B, Chand V, Groen H. Continued Afatinib (A) With the Addition of Cetuximab (C) After Progression on Afatinib in Patients With Acquired Resistance (AR) to Gefitinib (G) or Erlotinib (E) Metastatic Non-Small Cell Lung Cancer. International Journal Of Radiation Oncology • Biology • Physics 2014, 90: s39-s40. DOI: 10.1016/j.ijrobp.2014.08.220.Peer-Reviewed Original ResearchAcquired Resistance of EGFR-Mutant Lung Adenocarcinomas to Afatinib plus Cetuximab Is Associated with Activation of mTORC1
Pirazzoli V, Nebhan C, Song X, Wurtz A, Walther Z, Cai G, Zhao Z, Jia P, de Stanchina E, Shapiro EM, Gale M, Yin R, Horn L, Carbone DP, Stephens PJ, Miller V, Gettinger S, Pao W, Politi K. Acquired Resistance of EGFR-Mutant Lung Adenocarcinomas to Afatinib plus Cetuximab Is Associated with Activation of mTORC1. Cell Reports 2014, 7: 999-1008. PMID: 24813888, PMCID: PMC4074596, DOI: 10.1016/j.celrep.2014.04.014.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinomaAdenocarcinoma of LungAfatinibAnimalsAntibodies, Monoclonal, HumanizedAntineoplastic Combined Chemotherapy ProtocolsCell Line, TumorCetuximabDrug Resistance, NeoplasmErbB ReceptorsHumansLung NeoplasmsMechanistic Target of Rapamycin Complex 1MiceMice, NudeMice, TransgenicMultiprotein ComplexesMutationQuinazolinesRandom AllocationTOR Serine-Threonine KinasesXenograft Model Antitumor AssaysConceptsTyrosine kinase inhibitorsFirst-generation tyrosine kinase inhibitorEGFR-mutant lung adenocarcinomaLung adenocarcinomaMechanisms of resistanceEGFR antibody cetuximabPotential therapeutic strategyBiopsy specimensAntibody cetuximabDrug combinationsMouse modelTherapeutic strategiesAfatinibAddition of rapamycinCetuximabDual inhibitionAcquired ResistanceKinase inhibitorsGenomic alterationsAdenocarcinomaPatientsActivationGenomic mechanismsDrugsMTORC1 activation
2011
Upregulated stromal EGFR and vascular remodeling in mouse xenograft models of angiogenesis inhibitor–resistant human lung adenocarcinoma
Cascone T, Herynk MH, Xu L, Du Z, Kadara H, Nilsson MB, Oborn CJ, Park YY, Erez B, Jacoby JJ, Lee JS, Lin HY, Ciardiello F, Herbst RS, Langley RR, Heymach JV. Upregulated stromal EGFR and vascular remodeling in mouse xenograft models of angiogenesis inhibitor–resistant human lung adenocarcinoma. Journal Of Clinical Investigation 2011, 121: 1313-1328. PMID: 21436589, PMCID: PMC3070607, DOI: 10.1172/jci42405.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinomaAngiogenesis InhibitorsAnimalsAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedApoptosisBevacizumabCell Line, TumorDrug Resistance, NeoplasmErbB ReceptorsGene Expression ProfilingHumansLung NeoplasmsMaleMiceMice, NudeNeovascularization, PathologicRNA, MessengerRNA, NeoplasmStromal CellsUp-RegulationVascular Endothelial Growth Factor AVascular Endothelial Growth Factor Receptor-2Xenograft Model Antitumor AssaysConceptsMouse xenograft modelHuman lung adenocarcinomaTumor cellsPrimary resistanceLung adenocarcinomaXenograft modelFGFR pathwayProgression-free survivalVEGF inhibitor bevacizumabEndothelium of tumorsInhibitors of angiogenesisCombination regimensTreatment of cancerVEGF inhibitorsPericyte coverageAntiangiogenic therapyVascular remodelingAngiogenesis inhibitorsTherapeutic efficacyTumor growthStromal pathwaysClinical useEGFRAcquired ResistanceEGFR pathway
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