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 inhibitionEP.07C.10 Real-World Outcomes of Patients Treated with Neoadjuvant Immunotherapy for Resectable Non-Small Cell Lung Cancer
Ermer T, Kim S, Goldberg S, Zolfaghari E, Blasberg J, Boffa D, Herbst R, Politi K, Schalper K, Dacic S, Woodard G. EP.07C.10 Real-World Outcomes of Patients Treated with Neoadjuvant Immunotherapy for Resectable Non-Small Cell Lung Cancer. Journal Of Thoracic Oncology 2024, 19: s543-s544. DOI: 10.1016/j.jtho.2024.09.1007.Peer-Reviewed Original ResearchChitinase 3-like-1 (CHI3L1) in the pathogenesis of epidermal growth factor receptor mutant non-small cell lung cancer
Kamle S, Ma B, Schor G, Bailey M, Pham B, Cho I, Khan H, Azzoli C, Hofstetter M, Sadanaga T, Herbst R, Politi K, Lee C, Elias J. Chitinase 3-like-1 (CHI3L1) in the pathogenesis of epidermal growth factor receptor mutant non-small cell lung cancer. Translational Oncology 2024, 49: 102108. PMID: 39178575, PMCID: PMC11388375, DOI: 10.1016/j.tranon.2024.102108.Peer-Reviewed Original ResearchNon-small cell lung cancerEpidermal growth factor receptorTyrosine kinase inhibitorsEpidermal growth factor receptor mutant non-small cell lung cancerMutant non-small cell lung cancerEpidermal growth factor receptor axisCell lung cancerLung cancerTherapeutic resistanceDownstream targets of EGFRResistance to TKI therapyEpithelial cellsStimulated epidermal growth factor receptorWild type epidermal growth factor receptorTargeting of epidermal growth factor receptorActivating EGFR mutationsChitinase 3-like 1Progression free survivalInduce tumor cell deathEpidermal growth factor receptor activationEffects of EGFR activationInhibited pulmonary metastasisTumor cell deathResponse to treatmentGrowth factor receptorAuthor Correction: Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer
Robichaux J, Elamin Y, Tan Z, Carter B, Zhang S, Liu S, Li S, Chen T, Poteete A, Estrada-Bernal A, Le A, Truini A, Nilsson M, Sun H, Roarty E, Goldberg S, Brahmer J, Altan M, Lu C, Papadimitrakopoulou V, Politi K, Doebele R, Wong K, Heymach J. Author Correction: Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer. Nature Medicine 2024, 30: 2694-2695. PMID: 39164519, DOI: 10.1038/s41591-024-03178-1.Peer-Reviewed Original ResearchASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts.
Hu B, Wiesehöfer M, de Miguel F, Liu Z, Chan L, Choi J, Melnick M, Arnal Estape A, Walther Z, Zhao D, Lopez-Giraldez F, Wurtz A, Cai G, Fan R, Gettinger S, Xiao A, Yan Q, Homer R, Nguyen D, Politi K. ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts. Cancer Research 2024, 84: 1303-1319. PMID: 38359163, PMCID: PMC11142404, DOI: 10.1158/0008-5472.can-23-0438.Peer-Reviewed Original ResearchTyrosine kinase inhibitorsPatient-derived xenograftsEGFR mutant lung cancerMutant lung cancerPre-treatment tumorsResidual diseaseDrug toleranceLung cancerResidual tumor cells in vivoEGFR mutant lung adenocarcinomaTyrosine kinase inhibitor osimertinibEGFR tyrosine kinase inhibitorsTyrosine kinase inhibitor treatmentTumor cells in vivoMutant lung adenocarcinomaMaximal tumor regressionTranscription factor Ascl1Drug-tolerant cellsTime of maximal responseEvidence of cellsCells in vivoOsimertinib treatmentTumor regressionSingle cell transcriptional profilingTumor cellsEGFR-Driven Lung Adenocarcinomas Co-opt Alveolar Macrophage Metabolism and Function to Support EGFR Signaling and Growth.
Kuhlmann-Hogan A, Cordes T, Xu Z, Kuna R, Traina K, Robles-Oteíza C, Ayeni D, Kwong E, Levy S, Globig A, Nobari M, Cheng G, Leibel S, Homer R, Shaw R, Metallo C, Politi K, Kaech S. EGFR-Driven Lung Adenocarcinomas Co-opt Alveolar Macrophage Metabolism and Function to Support EGFR Signaling and Growth. Cancer Discovery 2024, of1-of22. PMID: 38270272, DOI: 10.1158/2159-8290.cd-23-0434.Peer-Reviewed Original ResearchLung adenocarcinomaGM-CSFEGFR-mutant lung adenocarcinomaT cell-based immunotherapyTransformed epitheliumOncogenic signalingGM-CSF secretionProinflammatory immune responseSuppress tumor progressionLocal immunosuppressionStatin therapyTherapeutic combinationsNovel therapiesTumor cellsTumor progressionTumor growthLung cancerLung adenocarcinoma cellsEGFR phosphorylationImmune responseImmunological supportCancer cellsInflammatory functionsAlveolar macrophagesIncreased cholesterol synthesis
2023
PTEN 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 microenvironment
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 changes
2020
Drug Sensitivity and Allele‐specificity of First‐line Osimertinib Resistance EGFR Mutations
Starrett J, Guernet A, Cuomo M, Poels K, van Rosenburgh I, Nagelberg A, Farnsworth D, Price K, Khan H, Ashtekar K, Gaefele M, Ayeni D, Stewart T, Kuhlmann A, Kaech S, Unni A, Homer R, Lockwood W, Michor F, Goldberg S, Lemmon M, Smith P, Cross D, Politi K. Drug Sensitivity and Allele‐specificity of First‐line Osimertinib Resistance EGFR Mutations. The FASEB Journal 2020, 34: 1-1. DOI: 10.1096/fasebj.2020.34.s1.00612.Peer-Reviewed Original ResearchFirst-line osimertinibEGFR-mutant lung cancerMutant lung cancerOsimertinib treatmentEGFR-TKILung cancerEGFR mutationsTotal tumorsPreferred first-line therapySecondary mutationsThird-generation EGFR-TKIFirst-line osimertinib treatmentMichael Smith FoundationResistance EGFR mutationsFirst-line therapySecondary EGFR mutationGeneration EGFR-TKISubsequent treatment approachesTransgenic mouse modelLung cancer researchTumor volume changesCoronal MR imagesTumor volume measurementsNew Investigator AwardResistance mechanisms
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
2014
Thoracic Neoplasia: Carcinoma
Politi K, Dela Cruz C, Homer R. Thoracic Neoplasia: Carcinoma. 2014, 2677-2689. DOI: 10.1016/b978-0-12-386456-7.05310-7.ChaptersLung cancerLung cancer subtypesDifferent natural historyLung cancer biologyCancer deathMolecular subtypesMouse modelNew therapiesSurvival rateCancer subtypesNatural historyLung cancer genomeTumor samplesDiseaseCell linesCancer biologyTherapyOngoing studiesCancerSubtypesRecent knowledgeMolecular mechanismsSpecific subsetPatientsCarcinoma