Cross-species transcriptomic signatures predict response to MK2 inhibition in mouse models of chronic inflammation
Lucía Suárez-López, Bing Shui, Douglas K. Brubaker, Marza Hill, Alexander Bergendorf, Paul S. Changelian, Aisha Laguna, Alina Starchenko, Douglas A. Lauffenburger, Kevin M. Haigis
Abstract
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.