Cerdulatinib, a novel dual SYK/JAK kinase inhibitor, has broad anti-tumor activity in both ABC and GCB types of diffuse large B cell lymphoma

// Jiao Ma 1 , Wei Xing 2 , Greg Coffey 3 , Karen Dresser 2 , Kellie Lu 4 , Ailin Guo 5 , Gordana Raca 6 , Anjali Pandey 3 , Pamela Conley 3 , Hongbo Yu 2 , Y. Lynn Wang 5 1 Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA 2 Department of Pathology, University of Massachusetts Memorial Medical Center and Medical School, Worcester, MA, USA 3 Department of Biology, Portola Pharmaceuticals, Inc., South San Francisco, CA, USA 4 University of Chicago Laboratory School, Chicago, IL, USA 5 Department of Pathology, Division of Genomic and Molecular Pathology, University of Chicago, Chicago, IL, USA 6 Department of Medicine, University of Chicago, IL, USA Correspondence to: Y. Lynn Wang, e-mail: ylwang@bsd.uchicago.edu Keywords: diffuse large B cell lymphoma, cerdulatinib, SYK, JAK-STAT, molecularly targeted therapy Received: May 27, 2015      Accepted: October 23, 2015      Published: November 05, 2015 ABSTRACT B-cell receptor (BCR) and JAK/STAT pathways play critical roles in diffuse large B-cell lymphoma (DLBCL). Herein, we investigated the anti-lymphoma activity of cerdulatinib, a novel compound that dually targets SYK and JAK/STAT pathways. On a tissue microarray of 62 primary DLBCL tumors, 58% expressed either phosphorylated SYK or STAT3 or both. SYK and STAT3 are also phosphorylated in a panel of eleven DLBCL cell lines although ABC and GCB subtypes exhibited different JAK/STAT and BCR signaling profiles. In both ABC and GCB cell lines, cerdulatinib induced apoptosis that was associated with caspase-3 and PARP cleavage. The compound also blocked G1/S transition and caused cell cycle arrest, accompanied by inhibition of RB phosphorylation and down-regulation of cyclin E. Phosphorylation of BCR components and STAT3 was sensitive to cerdulatinib in both ABC and GCB cell lines under stimulated conditions. Importantly, JAK/STAT and BCR signaling can be blocked by cerdulatinib in primary GCB and non-GCB DLBCL tumor cells that were accompanied by cell death. Our work provides mechanistic insights into the actions of cerdulatinib, suggesting that the drug has a broad anti-tumor activity in both ABC and GCB DLBCL, at least in part by inhibiting SYK and JAK pathways.