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MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I

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Item Type:Article
Title:MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I
Creators Name:Brägelmann, J. and Lorenz, C. and Borchmann, S. and Nishii, K. and Wegner, J. and Meder, L. and Ostendorp, J. and Ast, D.F. and Heimsoeth, A. and Nakasuka, T. and Hirabae, A. and Okawa, S. and Dammert, M.A. and Plenker, D. and Klein, S. and Lohneis, P. and Gu, J. and Godfrey, L.K. and Forster, J. and Trajkovic-Arsic, M. and Zillinger, T. and Haarmann, M. and Quaas, A. and Lennartz, S. and Schmiel, M. and D'Rozario, J. and Thomas, E.S. and Li, H. and Schmitt, C.A. and George, J. and Thomas, R.K. and von Karstedt, S. and Hartmann, G. and Büttner, R. and Ullrich, R.T. and Siveke, J.T. and Ohashi, K. and Schlee, M. and Sos, M.L.
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(+) 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.
Keywords:Signal Transducing Adaptor Proteins, Cell Cycle Checkpoints, Cell Death, Tumor Cell Line, Cytokines, DEAD Box Protein 58, ErbB Receptors, Neoplastic Gene Expression Regulation, Immune Evasion, Innate Immunity, Inflammation, Interferon Regulatory Factor-1, MAP Kinase Signaling System, Neoplasms, Oncogenes, Protein Kinase Inhibitors, Immunologic Receptors, Signal Transduction, Animals, Mice, Inbred C57BL Mice
Source:Nature Communications
Publisher:Nature Publishing Group
Page Range:5505
Date:17 September 2021
Official Publication:https://doi.org/10.1038/s41467-021-25728-8
PubMed:View item in PubMed

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