PKN1 is a novel therapeutic target to prevent graft-vs-host disease after allogeneic hematopoietic cell transplantation

Abstract We were the first to demonstrate that targeting JAK1/2 using baricitinib (BARI) and ruxolitinib (RUX) prevents treats GVHD while enhancing multi-lineage hematopoietic reconstitution graft-vs-leukemia (GvL) effect in mouse models of allogeneic cell transplantation (allo-HCT). However, unlike BARI, RUX fails completely prevent or treat GvHD. To elucidate mechanism underlying superiority BARI RUX, we performed both human kinome analyses. found but not is a potent inhibitor murine PKN1, suggesting preventing treating GvHD may result from off-target effects on PKN1 addition its known inhibitory JAK1/2. While function remains unexplored, has been suggested as protein kinase signaling pathways involving S1PR1/ PPP1R14A, LFA-1/STK4 LFA-1/RPH3A for immune adhesion/trafficking balance regulatory T cells effector cells. define role GvHD, examined if OTS167, inhibitor, alters downstream these candidate pathways. OTS167 significantly reduces phosphorylation PPP1R14A STK4 dose-dependent manner. Of note, RPH3A pRPH3A detectable In addition, vivo administration model allo-HCT (p<0.05). Furthermore, recipient mice transplanted with S1PR1 KO improved overall survival These data suggest S1PR1/PPP1R14A (and also which currently under investigation) are critical components inducing This research was supported by Alvin J. Siteman Cancer Center through The Foundation Barnes-Jewish Hospital.