Dual SYK/JAK inhibition overcomes ibrutinib resistance in chronic lymphocytic leukemia: Cerdulatinib, but not ibrutinib, induces apoptosis of tumor cells protected by the microenvironment
| Autor: | Anjali Pandey, Y. Lynn Wang, Pamela B. Conley, Pin Lu, Greg Coffey, Ailin Guo |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Chronic lymphocytic leukemia medicine.medical_treatment Syk Apoptosis Cell Separation JAK-STAT Targeted therapy chemistry.chemical_compound 0302 clinical medicine Piperidines immune system diseases hemic and lymphatic diseases Agammaglobulinaemia Tyrosine Kinase Tumor Cells Cultured Tumor Microenvironment SYK Sulfones biology breakpoint cluster region Protein-Tyrosine Kinases Oncology 030220 oncology & carcinogenesis Ibrutinib molecularly targeted therapy Research Paper Antineoplastic Agents 03 medical and health sciences medicine Humans Syk Kinase Bruton's tyrosine kinase Protein Kinase Inhibitors Cell Proliferation Janus Kinases Tumor microenvironment business.industry Adenine medicine.disease Leukemia Lymphocytic Chronic B-Cell Coculture Techniques Lymphoma cerdulatinib Pyrimidines 030104 developmental biology chemistry Drug Resistance Neoplasm Immunology biology.protein Cancer research Pyrazoles business CLL |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.14588 |
| Popis: | // Ailin Guo 1,* , Pin Lu 1,* , Greg Coffey 2 , Pamela Conley 2 , Anjali Pandey 2 and Y. Lynn Wang 1 1 Department of Pathology, Lymphoma Translational Pathology, University of Chicago, Chicago, IL, USA 2 Portola Pharmaceuticals, Inc., South San Francisco, CA, USA * These authors have contributed equally to this study Correspondence to: Y. Lynn Wang, email: // Keywords : CLL, cerdulatinib, SYK, JAK-STAT, molecularly targeted therapy Received : December 21, 2016 Accepted : January 01, 2017 Published : January 10, 2017 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 BTK C481S -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. |
| Databáze: | OpenAIRE |
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