The kinase inhibitors R406 and GS-9973 impair T cell functions and macrophage-mediated anti-tumor activity of rituximab in chronic lymphocytic leukemia patients
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 s...
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todo:paper_03407004_v66_n4_p461_Colado2023-10-03T15:25:50Z The kinase inhibitors R406 and GS-9973 impair T cell functions and macrophage-mediated anti-tumor activity of rituximab in chronic lymphocytic leukemia patients Colado, A. Almejún, M.B. Podaza, E. Risnik, D. Stanganelli, C. Elías, E.E. Dos Santos, P. Slavutsky, I. Fernández Grecco, H. Cabrejo, M. Bezares, R.F. Giordano, M. Gamberale, R. Borge, M. 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 protein kinase Syk protein kinase ZAP 70 pyrazine derivative pyridine derivative rituximab antineoplastic activity Article cancer patient CD4+ T lymphocyte cell migration chronic lymphatic leukemia controlled study cytokine release human human cell lymphocyte activation lymphocyte function lymphocyte proliferation macrophage phagocytosis priority journal protein phosphorylation upregulation aged antagonists and inhibitors cell culture cell proliferation drug effects female immunology Leukemia, Lymphocytic, Chronic, B-Cell lymphocyte activation male metabolism middle aged phosphorylation T lymphocyte very elderly Aged Aged, 80 and over Cell Proliferation Cells, Cultured Female Humans Indazoles Leukemia, Lymphocytic, Chronic, B-Cell Lymphocyte Activation Macrophages Male Middle Aged Oxazines Phagocytosis Phosphorylation Pyrazines Pyridines Receptors, Antigen, T-Cell Rituximab Syk Kinase T-Lymphocytes ZAP-70 Protein-Tyrosine Kinase 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. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_03407004_v66_n4_p461_Colado |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
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 protein kinase Syk protein kinase ZAP 70 pyrazine derivative pyridine derivative rituximab antineoplastic activity Article cancer patient CD4+ T lymphocyte cell migration chronic lymphatic leukemia controlled study cytokine release human human cell lymphocyte activation lymphocyte function lymphocyte proliferation macrophage phagocytosis priority journal protein phosphorylation upregulation aged antagonists and inhibitors cell culture cell proliferation drug effects female immunology Leukemia, Lymphocytic, Chronic, B-Cell lymphocyte activation male metabolism middle aged phosphorylation T lymphocyte very elderly Aged Aged, 80 and over Cell Proliferation Cells, Cultured Female Humans Indazoles Leukemia, Lymphocytic, Chronic, B-Cell Lymphocyte Activation Macrophages Male Middle Aged Oxazines Phagocytosis Phosphorylation Pyrazines Pyridines Receptors, Antigen, T-Cell Rituximab Syk Kinase T-Lymphocytes ZAP-70 Protein-Tyrosine Kinase |
| spellingShingle |
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 protein kinase Syk protein kinase ZAP 70 pyrazine derivative pyridine derivative rituximab antineoplastic activity Article cancer patient CD4+ T lymphocyte cell migration chronic lymphatic leukemia controlled study cytokine release human human cell lymphocyte activation lymphocyte function lymphocyte proliferation macrophage phagocytosis priority journal protein phosphorylation upregulation aged antagonists and inhibitors cell culture cell proliferation drug effects female immunology Leukemia, Lymphocytic, Chronic, B-Cell lymphocyte activation male metabolism middle aged phosphorylation T lymphocyte very elderly Aged Aged, 80 and over Cell Proliferation Cells, Cultured Female Humans Indazoles Leukemia, Lymphocytic, Chronic, B-Cell Lymphocyte Activation Macrophages Male Middle Aged Oxazines Phagocytosis Phosphorylation Pyrazines Pyridines Receptors, Antigen, T-Cell Rituximab Syk Kinase T-Lymphocytes ZAP-70 Protein-Tyrosine Kinase Colado, A. Almejún, M.B. Podaza, E. Risnik, D. Stanganelli, C. Elías, E.E. Dos Santos, P. Slavutsky, I. Fernández Grecco, H. Cabrejo, M. Bezares, R.F. Giordano, M. Gamberale, R. Borge, M. The kinase inhibitors R406 and GS-9973 impair T cell functions and macrophage-mediated anti-tumor activity of rituximab in chronic lymphocytic leukemia patients |
| topic_facet |
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 protein kinase Syk protein kinase ZAP 70 pyrazine derivative pyridine derivative rituximab antineoplastic activity Article cancer patient CD4+ T lymphocyte cell migration chronic lymphatic leukemia controlled study cytokine release human human cell lymphocyte activation lymphocyte function lymphocyte proliferation macrophage phagocytosis priority journal protein phosphorylation upregulation aged antagonists and inhibitors cell culture cell proliferation drug effects female immunology Leukemia, Lymphocytic, Chronic, B-Cell lymphocyte activation male metabolism middle aged phosphorylation T lymphocyte very elderly Aged Aged, 80 and over Cell Proliferation Cells, Cultured Female Humans Indazoles Leukemia, Lymphocytic, Chronic, B-Cell Lymphocyte Activation Macrophages Male Middle Aged Oxazines Phagocytosis Phosphorylation Pyrazines Pyridines Receptors, Antigen, T-Cell Rituximab Syk Kinase T-Lymphocytes ZAP-70 Protein-Tyrosine Kinase |
| description |
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. |
| format |
JOUR |
| author |
Colado, A. Almejún, M.B. Podaza, E. Risnik, D. Stanganelli, C. Elías, E.E. Dos Santos, P. Slavutsky, I. Fernández Grecco, H. Cabrejo, M. Bezares, R.F. Giordano, M. Gamberale, R. Borge, M. |
| author_facet |
Colado, A. Almejún, M.B. Podaza, E. Risnik, D. Stanganelli, C. Elías, E.E. Dos Santos, P. Slavutsky, I. Fernández Grecco, H. Cabrejo, M. Bezares, R.F. Giordano, M. Gamberale, R. Borge, M. |
| author_sort |
Colado, A. |
| title |
The kinase inhibitors R406 and GS-9973 impair T cell functions and macrophage-mediated anti-tumor activity of rituximab in chronic lymphocytic leukemia patients |
| title_short |
The kinase inhibitors R406 and GS-9973 impair T cell functions and macrophage-mediated anti-tumor activity of rituximab in chronic lymphocytic leukemia patients |
| title_full |
The kinase inhibitors R406 and GS-9973 impair T cell functions and macrophage-mediated anti-tumor activity of rituximab in chronic lymphocytic leukemia patients |
| title_fullStr |
The kinase inhibitors R406 and GS-9973 impair T cell functions and macrophage-mediated anti-tumor activity of rituximab in chronic lymphocytic leukemia patients |
| title_full_unstemmed |
The kinase inhibitors R406 and GS-9973 impair T cell functions and macrophage-mediated anti-tumor activity of rituximab in chronic lymphocytic leukemia patients |
| title_sort |
kinase inhibitors r406 and gs-9973 impair t cell functions and macrophage-mediated anti-tumor activity of rituximab in chronic lymphocytic leukemia patients |
| url |
http://hdl.handle.net/20.500.12110/paper_03407004_v66_n4_p461_Colado |
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