Article ; Online: 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.
2015 Volume 6, Issue 41, Page(s) 43881–43896
Abstract: ... has a broad anti-tumor activity in both ABC and GCB DLBCL, at least in part by inhibiting SYK and JAK ... 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 ...
| 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. |
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| MeSH term(s) | Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Enzyme Inhibitors/pharmacology ; Flow Cytometry ; Humans ; Immunoblotting ; Immunohistochemistry ; Intracellular Signaling Peptides and Proteins/metabolism ; Janus Kinases/metabolism ; Lymphoma, Large B-Cell, Diffuse/pathology ; Protein-Tyrosine Kinases/metabolism ; Pyrimidines/pharmacology ; Signal Transduction/drug effects ; Sulfones/pharmacology ; Syk Kinase ; Tissue Array Analysis |
| Chemical Substances | 4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide ; Antineoplastic Agents ; Enzyme Inhibitors ; Intracellular Signaling Peptides and Proteins ; Pyrimidines ; Sulfones ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Janus Kinases (EC 2.7.10.2) ; SYK protein, human (EC 2.7.10.2) ; Syk Kinase (EC 2.7.10.2) |
| Language | English |
| Publishing date | 2015-12-22 |
| Publishing country | United States |
| Document type | Journal Article |
| ZDB-ID | 2560162-3 |
| ISSN | 1949-2553 ; 1949-2553 |
| ISSN (online) | 1949-2553 |
| ISSN | 1949-2553 |
| DOI | 10.18632/oncotarget.6316 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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