ArticleNature communications2021
MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I.
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Article in Nature communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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52citing papers in PubMed
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52 citing papers in PubMed, 72 citations in OpenAlex.
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Authors and funding
39 authors at 6 institutions in 5 countries.
Johannes Brägelmann *Molecular Pathology, Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany. johannes.braegelmann@uni-koeln.de.ORCID 0000-0002-1306-2169
Carina Lorenz *Molecular Pathology, Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.
Sven BorchmannCenter for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.
Kazuya NishiiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Julia WegnerInstitute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.ORCID 0000-0001-8103-8040
Lydia MederCenter for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.
Jenny OstendorpMolecular Pathology, Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.
David F AstMolecular Pathology, Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.
Alena HeimsoethMolecular Pathology, Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.
Takamasa NakasukaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Atsuko HirabaeDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Sachi OkawaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Marcel A DammertMolecular Pathology, Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.ORCID 0000-0003-4269-7822
Dennis PlenkerCold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA.ORCID 0000-0003-3895-4064
Sebastian KleinElse-Kröner-Forschungskolleg Clonal Evolution in Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.
Philipp LohneisInstitute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.ORCID 0000-0002-4797-0018
Jianing GuInstitute for Developmental Cancer Therapeutics, West German Cancer Center, University Hospital Essen, Essen, Germany.
Laura K GodfreyInstitute for Developmental Cancer Therapeutics, West German Cancer Center, University Hospital Essen, Essen, Germany.
Jan ForsterDivision of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany.
Marija Trajkovic-ArsicInstitute for Developmental Cancer Therapeutics, West German Cancer Center, University Hospital Essen, Essen, Germany.
Thomas ZillingerInstitute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.ORCID 0000-0002-0866-4835
Mareike HaarmannMildred Scheel School of Oncology Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.
Alexander QuaasInstitute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.
Stefanie LennartzMolecular Pathology, Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.
Marcel SchmielDepartment of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.
Joshua D'RozarioDepartment of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.ORCID 0000-0002-3380-4801
Emily S ThomasDepartment of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.
Henry LiCrown Bioscience, San Diego, CA, USA.ORCID 0000-0002-4673-1234
Clemens A SchmittDepartment of Hematology, Oncology and Tumor Immunology, Charité - University Medical Center, Virchow Campus, and Molekulares Krebsforschungszentrum, Berlin, Germany.ORCID 0000-0002-4731-2226
Julie GeorgeDepartment of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.ORCID 0000-0002-4272-3683
Roman K ThomasDepartment of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.
Silvia von KarstedtDepartment of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.ORCID 0000-0002-7816-5919
Gunther HartmannInstitute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.ORCID 0000-0003-1021-2018
Reinhard BüttnerInstitute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.ORCID 0000-0001-8806-4786
Roland T UllrichCenter for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.
Jens T SivekeInstitute for Developmental Cancer Therapeutics, West German Cancer Center, University Hospital Essen, Essen, Germany.ORCID 0000-0002-8772-4778
Kadoaki OhashiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Martin SchleeInstitute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.ORCID 0000-0003-3671-7639
Martin L SosMolecular Pathology, Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany. martin.sos@uni-koeln.de.ORCID 0000-0002-2868-100X
University of Cologne · DEGerman Cancer Research Center · DEOkayama University · JPUniversity Hospital Bonn · DECold Spring Harbor Laboratory · USJohannes Kepler University of Linz · AT
Funding
Single-Cell Biology Shared ResourceP30CA045508 · NCI · COLD SPRING HARBOR LABORATORY · PI John Edward Moses · 1987 to 2026
$118.9MNCI NIH HHS P30 CA045508
Abstract
Kinase inhibitors suppress the growth of oncogene driven cancer but also enforce the selection of treatment resistant cells that are thought to promote tumor relapse in patients. Here, we report transcriptomic and functional genomics analyses of cells and tumors within their microenvironment across different genotypes that persist during kinase inhibitor treatment. We uncover a conserved, MAPK/IRF1-mediated inflammatory response in tumors that undergo stemness- and senescence-associated reprogramming. In these tumor cells, activation of the innate immunity sensor RIG-I via its agonist IVT4, triggers an interferon and a pro-apoptotic response that synergize with concomitant kinase inhibition. In humanized lung cancer xenografts and a syngeneic Egfr-driven lung cancer model these effects translate into reduction of exhausted CD8
Indexed as
Immunity, InnateMAP Kinase Signaling SystemAdaptor Proteins, Signal TransducingAnimalsCell Cycle CheckpointsCell DeathCell Line, TumorCytokinesDEAD Box Protein 58ErbB ReceptorsFemaleGene Expression Regulation, NeoplasticHumansImmune EvasionInflammationInterferon Regulatory Factor-1Adaptor Proteins, Signal TransducingCytokinesDEAD Box Protein 58ErbB ReceptorsInterferon Regulatory Factor-1IRF1 protein, humanMAVS protein, humanProtein Kinase InhibitorsReceptors, ImmunologicRIGI protein, human
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