The kinase inhibitors R406 and GS-9973 impair T cell functions and macrophage-mediated anti-tumor activity of rituximab in chronic lymphocytic leukemia patients
| العنوان: | The kinase inhibitors R406 and GS-9973 impair T cell functions and macrophage-mediated anti-tumor activity of rituximab in chronic lymphocytic leukemia patients |
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| المؤلفون: | Almejún, María Belén, Giordano, Mirta Nilda, Gamberale, Romina, Borge, Mercedes |
| سنة النشر: | 2017 |
| المجموعة: | Biblioteca Digital FCEN-UBA (Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires) |
| مصطلحات موضوعية: | BCR-associated kinase inhibitors, Chronic lymphocytic leukemia, GS-9973, R406, Syk inhibitors, CD40 ligand, chemokine receptor CCR7, chemokine receptor CXCR4, entospletinib, fostamatinib, gamma interferon, interleukin 10, interleukin 4, protein kinase Syk, protein kinase ZAP 70, rituximab, 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo(1,2-a)pyrazin-8-amine, indazole derivative, lymphocyte antigen receptor, N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine, oxazine derivative, pyrazine derivative, pyridine derivative, antineoplastic activity, Article, cancer patient, CD4+ T lymphocyte, cell migration, chronic lymphatic leukemia, controlled study |
| الوصف: | Small molecules targeting kinases involved in B cell receptor signaling are showing encouraging clinical activity in chronic lymphocytic leukemia (CLL) patients. Fostamatinib (R406) and entospletinib (GS-9973) are ATP-competitive inhibitors designed to target spleen tyrosine kinase (Syk) that have shown clinical activity with acceptable toxicity in trials with CLL patients. Preclinical studies with these inhibitors in CLL have focused on their effect in patient-derived leukemic B cells. In this work we show that clinically relevant doses of R406 and GS-9973 impaired the activation and proliferation of T cells from CLL patients. This effect could not be ascribed to Syk-inhibition given that we show that T cells from CLL patients do not express Syk protein. Interestingly, ζ-chain-associated protein kinase (ZAP)-70 phosphorylation was diminished by both inhibitors upon TCR stimulation on T cells. In addition, we found that both agents reduced macrophage-mediated phagocytosis of rituximab-coated CLL cells. Overall, these results suggest that in CLL patients treated with R406 or GS-9973 T cell functions, as well as macrophage-mediated anti-tumor activity of rituximab, might be impaired. The potential consequences for CLL-treated patients are discussed. © 2016, Springer-Verlag Berlin Heidelberg. ; Fil:Almejún, M.B. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. ; Fil:Giordano, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. ; Fil:Gamberale, R. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. ; Fil:Borge, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. |
| نوع الوثيقة: | other/unknown material |
| اللغة: | unknown |
| العلاقة: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_03407004_v66_n4_p461_ColadoTest; http://hdl.handle.net/20.500.12110/paper_03407004_v66_n4_p461_ColadoTest |
| الإتاحة: | https://doi.org/20.500.12110/paper_03407004_v66_n4_p461_ColadoTest https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_03407004_v66_n4_p461_ColadoTest https://hdl.handle.net/20.500.12110/paper_03407004_v66_n4_p461_ColadoTest |
| رقم الانضمام: | edsbas.40E595A1 |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |