title: The Dual Syk/JAK Inhibitor Cerdulatinib Antagonizes B-cell Receptor and Microenvironmental Signaling in Chronic Lymphocytic Leukemia.
abstract: 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 treatedin vitrowith 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 venetoclaxin vitroto 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.
authors.affiliation: Cancer Sciences Unit (MP824), University of Southampton, Southampton, United Kingdom.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Blunt
authors.affiliation: Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Stefan
authors.initials: S
authors.lastname: Koehrer
authors.affiliation: Cancer Sciences Unit (MP824), University of Southampton, Southampton, United Kingdom.
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Dobson
authors.affiliation: Cancer Sciences Unit (MP824), University of Southampton, Southampton, United Kingdom.
authors.forename: Marta
authors.initials: M
authors.lastname: Larrayoz
authors.affiliation: Cancer Sciences Unit (MP824), University of Southampton, Southampton, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wilmore
authors.affiliation: Cancer Sciences Unit (MP824), University of Southampton, Southampton, United Kingdom.
authors.forename: Alice
authors.initials: A
authors.lastname: Hayman
authors.affiliation: Cancer Sciences Unit (MP824), University of Southampton, Southampton, United Kingdom.
authors.forename: Jack
authors.initials: J
authors.lastname: Parnell
authors.affiliation: Cancer Sciences Unit (MP824), University of Southampton, Southampton, United Kingdom.
authors.forename: Lindsay D
authors.initials: LD
authors.lastname: Smith
authors.affiliation: Cancer Sciences Unit (MP824), University of Southampton, Southampton, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Davies
authors.affiliation: Cancer Sciences Unit (MP824), University of Southampton, Southampton, United Kingdom.
authors.forename: Peter W M
authors.initials: PWM
authors.lastname: Johnson
authors.affiliation: Portola Pharmaceuticals, South San Francisco, California.
authors.forename: Pamela B
authors.initials: PB
authors.lastname: Conley
authors.affiliation: Portola Pharmaceuticals, South San Francisco, California.
authors.forename: Anjali
authors.initials: A
authors.lastname: Pandey
authors.affiliation: Cancer Sciences Unit (MP824), University of Southampton, Southampton, United Kingdom.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Strefford
authors.affiliation: Cancer Sciences Unit (MP824), University of Southampton, Southampton, United Kingdom.
authors.forename: Freda K
authors.initials: FK
authors.lastname: Stevenson
authors.affiliation: Cancer Sciences Unit (MP824), University of Southampton, Southampton, United Kingdom.
authors.forename: Graham
authors.initials: G
authors.lastname: Packham
authors.affiliation: Cancer Sciences Unit (MP824), University of Southampton, Southampton, United Kingdom.|Haematology Department at the University Hospital Southampton NHS Trust, Southampton, United Kingdom.
authors.forename: Francesco
authors.initials: F
authors.lastname: Forconi
authors.affiliation: Portola Pharmaceuticals, South San Francisco, California.
authors.forename: Greg P
authors.initials: GP
authors.lastname: Coffey
authors.affiliation: Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Burger
authors.affiliation: Cancer Sciences Unit (MP824), University of Southampton, Southampton, United Kingdom. A.Steele@soton.ac.uk.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Steele
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000075242:Janus Kinase Inhibitors / Q000008:administration & dosage; D053612:Janus Kinases / Q000037:antagonists & inhibitors; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D009363:Neoplasm Proteins / Q000235:genetics; D010880:Piperidines; D051562:Proto-Oncogene Proteins c-bcr / Q000037:antagonists & inhibitors / Q000235:genetics; D011720:Pyrazoles / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage*; D011947:Receptors, Antigen, B-Cell / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage; D013450:Sulfones / Q000008:administration & dosage*; D000072377:Syk Kinase / Q000037:antagonists & inhibitors; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: C000595259:4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide; D019086:Bridged Bicyclo Compounds, Heterocyclic; D000075242:Janus Kinase Inhibitors; D009363:Neoplasm Proteins; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D011947:Receptors, Antigen, B-Cell; D013449:Sulfonamides; D013450:Sulfones; C551803:ibrutinib; D053612:Janus Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr; D000225:Adenine; C579720:venetoclax