title: 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.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Jiao
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Pathology, University of Massachusetts Memorial Medical Center and Medical School, Worcester, MA, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Xing
authors.affiliation: Department of Biology, Portola Pharmaceuticals, Inc., South San Francisco, CA, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Coffey
authors.affiliation: Department of Pathology, University of Massachusetts Memorial Medical Center and Medical School, Worcester, MA, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Dresser
authors.affiliation: University of Chicago Laboratory School, Chicago, IL, USA.
authors.forename: Kellie
authors.initials: K
authors.lastname: Lu
authors.affiliation: Department of Pathology, Division of Genomic and Molecular Pathology, University of Chicago, Chicago, IL, USA.
authors.forename: Ailin
authors.initials: A
authors.lastname: Guo
authors.affiliation: Department of Medicine, University of Chicago, IL, USA.
authors.forename: Gordana
authors.initials: G
authors.lastname: Raca
authors.affiliation: Department of Biology, Portola Pharmaceuticals, Inc., South San Francisco, CA, USA.
authors.forename: Anjali
authors.initials: A
authors.lastname: Pandey
authors.affiliation: Department of Biology, Portola Pharmaceuticals, Inc., South San Francisco, CA, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Conley
authors.affiliation: Department of Pathology, University of Massachusetts Memorial Medical Center and Medical School, Worcester, MA, USA.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Pathology, Division of Genomic and Molecular Pathology, University of Chicago, Chicago, IL, USA.
authors.forename: Y Lynn
authors.initials: YL
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013450:Sulfones / Q000494:pharmacology*; D000072377:Syk Kinase; D046888:Tissue Array Analysis
chemical_list: C000595259:4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011743:Pyrimidines; D013450:Sulfones; D011505:Protein-Tyrosine Kinases; D053612:Janus Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase
keywords: JAK-STAT; SYK; cerdulatinib; diffuse large B cell lymphoma; molecularly targeted therapy