Cross-species transcriptomic signatures predict response to MK2 inhibition in mouse models of chronic inflammation
Lucia Suarez-Lopez,
Bing Shui,
Douglas K. Brubaker,
Marza Hill,
Alexander Bergendorf,
Paul S. Changelian,
Aisha Laguna,
Alina Starchenko,
Douglas A. Lauffenburger,
Kevin M. Haigis
Affiliations
Lucia Suarez-Lopez
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02215, USA
Bing Shui
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02215, USA
Douglas K. Brubaker
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47906, USA; Regenstrief Center for Healthcare Engineering, Purdue University, West Lafayette, IN 47906, USA
Marza Hill
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02215, USA
Alexander Bergendorf
Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47906, USA
Paul S. Changelian
Aclaris Therapeutics, Inc., 4320 Forest Park Avenue, St. Louis, MO 63108, USA
Aisha Laguna
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02215, USA
Alina Starchenko
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Douglas A. Lauffenburger
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Kevin M. Haigis
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02215, USA; Corresponding author
Summary: Inflammatory bowel diseases (IBDs) are genetically complex and exhibit significant inter-patient heterogeneity in disease presentation and therapeutic response. Here, we show that mouse models of IBD exhibit variable responses to inhibition of MK2, a pro-inflammatory serine/threonine kinase, and that MK2 inhibition suppresses inflammation by targeting inflammatory monocytes and neutrophils in murine models. Using a computational approach (TransComp-R) that allows for cross-species comparison of transcriptomic features, we identified an IBD patient subgroup that is predicted to respond to MK2 inhibition, and an independent preclinical model of chronic intestinal inflammation predicted to be non-responsive, which we validated experimentally. Thus, cross-species mouse-human translation approaches can help to identify patient subpopulations in which to deploy new therapies.
