2. Academic Validation
  3. RIP1 inhibition blocks inflammatory diseases but not tumor growth or metastases

RIP1 inhibition blocks inflammatory diseases but not tumor growth or metastases

  • Cell Death Differ. 2020 Jan;27(1):161-175. doi: 10.1038/s41418-019-0347-0.
Snahel Patel 1,  Joshua D Webster 2,  Eugene Varfolomeev 3,  Youngsu C Kwon 4,  Jason H Cheng 5,  Juan Zhang 4,  Debra L Dugger 6,  Kate E Wickliffe 6,  Allie Maltzman 6,  Swathi Sujatha-Bhaskar 7,  Pawan Bir Kohli 8 9,  Sreema Ramaswamy 8,  Gauri Deshmukh 10,  Bianca M Liederer 10,  Rina Fong 11,  Greg Hamilton 12,  Patrick Lupardus 11,  Patrick Caplazi 2,  Wyne P Lee 4,  Menno van Lookeren Campagne 7 13,  Adam Johnson 8,  Brent S McKenzie 4,  Melissa R Junttila 5,  Kim Newton 6,  Domagoj Vucic 14
Affiliations

Affiliations

  • 1 Department of Discovery Chemistry, Genentech, 1 DNA Way, South San Francisco, CA, 94080, USA. patel.snahel@gene.com.
  • 2 Department of Pathology, Genentech, 1 DNA Way, South San Francisco, CA, 94080, USA.
  • 3 Department of Early Discovery Biochemistry, Genentech, 1 DNA Way, South San Francisco, CA, 94080, USA.
  • 4 Department of Translational Immunology, Genentech, 1 DNA Way, South San Francisco, CA, 94080, USA.
  • 5 Department of Molecular Oncology, Genentech, 1 DNA Way, South San Francisco, CA, 94080, USA.
  • 6 Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, CA, 94080, USA.
  • 7 Departments of Immunology, Genentech, 1 DNA Way, South San Francisco, CA, 94080, USA.
  • 8 Department of Biochemical and Cellular Pharmacology, Genentech, 1 DNA Way, South San Francisco, CA, 94080, USA.
  • 9 Gilead, Foster City, CA, 94404, USA.
  • 10 Department of Drug Metabolism and Pharmacokinetics, Genentech, 1 DNA Way, South San Francisco, CA, 94080, USA.
  • 11 Department of Structural Biology, Genentech, 1 DNA Way, South San Francisco, CA, 94080, USA.
  • 12 Department of Discovery Chemistry, Genentech, 1 DNA Way, South San Francisco, CA, 94080, USA.
  • 13 Amgen, South San Francisco, CA, 94080, USA.
  • 14 Department of Early Discovery Biochemistry, Genentech, 1 DNA Way, South San Francisco, CA, 94080, USA. domagoj@gene.com.
PMID: 31101885 DOI: 10.1038/s41418-019-0347-0
Abstract

The kinase RIP1 acts in multiple signaling pathways to regulate inflammatory responses and it can trigger both Apoptosis and Necroptosis. Its kinase activity has been implicated in a range of inflammatory, neurodegenerative, and oncogenic diseases. Here, we explore the effect of inhibiting RIP1 genetically, using knock-in mice that express catalytically inactive RIP1 D138N, or pharmacologically, using the murine-potent inhibitor GNE684. Inhibition of RIP1 reduced collagen antibody-induced arthritis, and prevented skin inflammation caused by mutation of Sharpin, or colitis caused by deletion of Nemo from intestinal epithelial cells. Conversely, inhibition of RIP1 had no effect on tumor growth or survival in pancreatic tumor models driven by mutant Kras, nor did it reduce lung metastases in a B16 melanoma model. Collectively, our data emphasize a role for the kinase activity of RIP1 in certain inflammatory disease models, but question its relevance to tumor progression and metastases.

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