title: Dual SYK/JAK inhibition overcomes ibrutinib resistance in chronic lymphocytic leukemia: Cerdulatinib, but not ibrutinib, induces apoptosis of tumor cells protected by the microenvironment.
abstract: Ibrutinib (BTK inhibitor) has generated remarkable responses in CLL. However, the drug, to a large extent, does not cause cell death directly and does not eradicate CLL malignant clones. Inability to eradicate CLL has fostered resistance generation. Once patients become resistant, they do poorly with a median survival of 3-4 months. Novel therapeutic strategies are needed to prevent resistance, improve treatment outcome and ultimately cure the disease. Herein, we explore dual targeting of the BCR and JAK-STAT pathways with a novel single agent, cerdulatinib, which selectively inhibits both SYK (a BCR component) and JAK kinases. We demonstrated that cerdulatinib delivered potent tumor inhibition in 60 primary CLL patient samples, especially in those with poor prognostic indicators. Importantly, cerdulatinib, but not ibrutinib, is able to overcome the support of microenvironment and induces CLL cell death at clinically achievable concentrations. Notably, cerdulatinib blocked proliferation of ibrutinib-resistant primary CLL cells and of BTKC481S-transfected/ibrutinib-resistant lymphoma cells. These anti-tumor effects are well correlated with the inhibition of BCR and JAK-STAT signaling and downstream inhibition of the functions of AKT, ERK and NFκB. Collectively, our results show that simultaneous targeting of BCR and JAK-STAT pathways is a more effective strategy relative to single BTK inhibition.
authors.affiliation: Department of Pathology, Lymphoma Translational Pathology, University of Chicago, Chicago, IL, USA.
authors.forename: Ailin
authors.initials: A
authors.lastname: Guo
authors.affiliation: Department of Pathology, Lymphoma Translational Pathology, University of Chicago, Chicago, IL, USA.
authors.forename: Pin
authors.initials: P
authors.lastname: Lu
authors.affiliation: Portola Pharmaceuticals, Inc., South San Francisco, CA, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Coffey
authors.affiliation: Portola Pharmaceuticals, Inc., South San Francisco, CA, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Conley
authors.affiliation: Portola Pharmaceuticals, Inc., South San Francisco, CA, USA.
authors.forename: Anjali
authors.initials: A
authors.lastname: Pandey
authors.affiliation: Department of Pathology, Lymphoma Translational Pathology, University of Chicago, Chicago, IL, USA.
authors.forename: Y Lynn
authors.initials: YL
authors.lastname: Wang
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology / Q000473:pathology*; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology*; D000072377:Syk Kinase / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
chemical_list: C000595259:4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide; D000970:Antineoplastic Agents; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D013450:Sulfones; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D053612:Janus Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D000225:Adenine
keywords: CLL; JAK-STAT; SYK; cerdulatinib; molecularly targeted therapy