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Ref Type Journal Article
PMID (27697994)
Authors Blunt MD, Koehrer S, Dobson RC, Larrayoz M, Wilmore S, Hayman A, Parnell J, Smith LD, Davies A, Johnson PWM, Conley PB, Pandey A, Strefford JC, Stevenson FK, Packham G, Forconi F, Coffey GP, Burger JA, Steele AJ
Title The Dual Syk/JAK Inhibitor Cerdulatinib Antagonizes B-cell Receptor and Microenvironmental Signaling in Chronic Lymphocytic Leukemia.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 23
Issue 9
Date 2017 May 01
URL
Abstract Text Purpose: B-cell receptor (BCR)-associated kinase inhibitors, such as ibrutinib, have revolutionized the treatment of chronic lymphocytic leukemia (CLL). However, these agents are not curative, and resistance is already emerging in a proportion of patients. IL4, expressed in CLL lymph nodes, can augment BCR signaling and reduce the effectiveness of BCR kinase inhibitors. Therefore, simultaneous targeting of the IL4- and BCR signaling pathways by cerdulatinib, a novel dual Syk/JAK inhibitor currently in clinical trials (NCT01994382), may improve treatment responses in patients.Experimental Design: PBMCs from patients with CLL were treated in vitro with cerdulatinib alone or in combination with venetoclax. Cell death, chemokine, and cell signaling assay were performed and analyzed by flow cytometry, immunoblotting, q-PCR, and ELISA as indicated.Results: At concentrations achievable in patients, cerdulatinib inhibited BCR- and IL4-induced downstream signaling in CLL cells using multiple readouts and prevented anti-IgM- and nurse-like cell (NLC)-mediated CCL3/CCL4 production. Cerdulatinib induced apoptosis of CLL cells, in a time- and concentration-dependent manner, and particularly in IGHV-unmutated samples with greater BCR signaling capacity and response to IL4, or samples expressing higher levels of sIgM, CD49d+, or ZAP70+ Cerdulatinib overcame anti-IgM, IL4/CD40L, or NLC-mediated protection by preventing upregulation of MCL-1 and BCL-XL; however, BCL-2 expression was unaffected. Furthermore, in samples treated with IL4/CD40L, cerdulatinib synergized with venetoclax in vitro to induce greater apoptosis than either drug alone.Conclusions: Cerdulatinib is a promising therapeutic for the treatment of CLL either alone or in combination with venetoclax, with the potential to target critical survival pathways in this currently incurable disease. Clin Cancer Res; 23(9); 2313-24. ©2016 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown chronic lymphocytic leukemia not applicable Cerdulatinib Preclinical - Patient cell culture Actionable In a preclinical study, Cerdulatinib (PRT062070) decreased BCR downstream signaling and chemokine secretion, and reduced viability of patient-derived chronic lymphocytic leukemia (CLL) cells in culture (PMID: 27697994). 27697994
Unknown unknown chronic lymphocytic leukemia not applicable Cerdulatinib + Venetoclax Preclinical - Patient cell culture Actionable In a preclinical study, the combination of Cerdulatinib (PRT062070) and Venclexta (venetoclax) worked synergistically to induce apoptosis of patient-derived chronic lymphocytic leukemia cells in culture, and resulted in decreased cell viability compared to either drug as a single agent (PMID: 27697994). 27697994