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
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Jiao Ma1, Wei Xing2, Greg Coffey3, Karen Dresser2, Kellie Lu4, Ailin Guo5, Gordana Raca6, Anjali Pandey3, Pamela Conley3, Hongbo Yu2, Y. Lynn Wang5
1Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA
2Department of Pathology, University of Massachusetts Memorial Medical Center and Medical School, Worcester, MA, USA
3Department of Biology, Portola Pharmaceuticals, Inc., South San Francisco, CA, USA
4University of Chicago Laboratory School, Chicago, IL, USA
5Department of Pathology, Division of Genomic and Molecular Pathology, University of Chicago, Chicago, IL, USA
6Department of Medicine, University of Chicago, IL, USA
Y. Lynn Wang, e-mail: [email protected]
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
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.
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