Braegelmann, Johannes, Lorenz, Carina, Borchmann, Sven ORCID: 0000-0001-6662-6864, Nishii, Kazuya, Wegner, Julia ORCID: 0000-0001-8103-8040, Meder, Lydia, Ostendorp, Jenny, Ast, David F., Heimsoeth, Alena, Nakasuka, Takamasa, Hirabae, Atsuko, Okawa, Sachi, Dammert, Marcel A., Plenker, Dennis, Klein, Sebastian ORCID: 0000-0002-2188-9377, Lohneis, Philipp, Gu, Jianing, Godfrey, Laura K., Forster, Jan, Trajkovic-Arsic, Marija, Zillinger, Thomas, Haarmann, Mareike, Quaas, Alexander, Lennartz, Stefanie, Schmiel, Marcel, D'Rozario, Joshua, Thomas, Emily S., Li, Henry, Schmitt, Clemens A. ORCID: 0000-0002-4731-2226, George, Julie, Thomas, Roman K., von Karstedt, Silvia, Hartmann, Gunther, Buettner, Reinhard, Ullrich, Roland T., Siveke, Jens T., Ohashi, Kadoaki, Schlee, Martin ORCID: 0000-0003-3671-7639 and Sos, Martin L. (2021). MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I. Nat. Commun., 12 (1). BERLIN: NATURE PORTFOLIO. ISSN 2041-1723

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Abstract

Kinase inhibitors are widely used to treat cancer, however patients frequently develop resistance. Here, the authors investigate adaption mechanisms during drug persistence and show that stimulation of the innate immunity sensor RIG-I enhances cancer cell death when combined with kinase inhibition. 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(+) T cells and robust tumor shrinkage. Overall, the mechanistic understanding of MAPK/IRF1-mediated intratumoral reprogramming may ultimately prolong the efficacy of targeted drugs in genetically defined cancer patients.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Braegelmann, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lorenz, CarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borchmann, SvenUNSPECIFIEDorcid.org/0000-0001-6662-6864UNSPECIFIED
Nishii, KazuyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wegner, JuliaUNSPECIFIEDorcid.org/0000-0001-8103-8040UNSPECIFIED
Meder, LydiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ostendorp, JennyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ast, David F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heimsoeth, AlenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nakasuka, TakamasaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hirabae, AtsukoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Okawa, SachiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dammert, Marcel A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Plenker, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klein, SebastianUNSPECIFIEDorcid.org/0000-0002-2188-9377UNSPECIFIED
Lohneis, PhilippUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gu, JianingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Godfrey, Laura K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Forster, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trajkovic-Arsic, MarijaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zillinger, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haarmann, MareikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Quaas, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lennartz, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmiel, MarcelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
D'Rozario, JoshuaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, Emily S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, HenryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitt, Clemens A.UNSPECIFIEDorcid.org/0000-0002-4731-2226UNSPECIFIED
George, JulieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, Roman K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Karstedt, SilviaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hartmann, GuntherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ullrich, Roland T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Siveke, Jens T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ohashi, KadoakiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schlee, MartinUNSPECIFIEDorcid.org/0000-0003-3671-7639UNSPECIFIED
Sos, Martin L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-603325
DOI: 10.1038/s41467-021-25728-8
Journal or Publication Title: Nat. Commun.
Volume: 12
Number: 1
Date: 2021
Publisher: NATURE PORTFOLIO
Place of Publication: BERLIN
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CANCER-CELLS; RESISTANCE; SENESCENCE; BRAF; MELANOMA; THERAPY; MIMICRY; GENES; STATE; RNAMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60332

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