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" (2017) Cancer Immunology, Immunotherapy. 66(4):461-473
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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.


Documento: Artículo
Título:The kinase inhibitors R406 and GS-9973 impair T cell functions and macrophage-mediated anti-tumor activity of rituximab in chronic lymphocytic leukemia patients
Autor: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.
Filiación:Laboratorio de Inmunología Oncológica, Instituto de Medicina Experimental (IMEX)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Academia Nacional de Medicina (ANM), Pacheco de Melo 3081, Buenos Aires, 1425, Argentina
Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
Servicio de Patología Molecular, Instituto de Investigaciones Hematológicas-ANM, Buenos Aires, Argentina
Laboratorio de Genética de Neoplasias Linfoides, IMEX-CONICET-ANM, Buenos Aires, Argentina
Departamento de Hematología, Sanatorio Julio Méndez, Buenos Aires, Argentina
Sección de Hematología, Hospital General de Agudos Dr. Teodoro Álvarez, Buenos Aires, Argentina
Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
Palabras clave: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
Página de inicio:461
Página de fin:473
Título revista:Cancer Immunology, Immunotherapy
Título revista abreviado:Cancer Immunol. Immunother.
CAS:CD40 ligand, 226713-27-5; chemokine receptor CCR7, 231617-75-7; chemokine receptor CXCR4, 188900-71-2; entospletinib, 1229208-44-9; fostamatinib, 901119-35-5; gamma interferon, 82115-62-6; protein kinase Syk, 138674-26-7; protein kinase ZAP 70, 148047-34-1; rituximab, 174722-31-7; 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo(1,2-a)pyrazin-8-amine; Indazoles; N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine; Oxazines; Pyrazines; Pyridines; Receptors, Antigen, T-Cell; Rituximab; Syk Kinase; ZAP-70 Protein-Tyrosine Kinase


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---------- APA ----------
Colado, A., Almejún, M.B., Podaza, E., Risnik, D., Stanganelli, C., Elías, E.E., Dos Santos, P.,..., Borge, M. (2017) . The kinase inhibitors R406 and GS-9973 impair T cell functions and macrophage-mediated anti-tumor activity of rituximab in chronic lymphocytic leukemia patients. Cancer Immunology, Immunotherapy, 66(4), 461-473.
---------- CHICAGO ----------
Colado, A., Almejún, M.B., Podaza, E., Risnik, D., Stanganelli, C., Elías, E.E., et al. "The kinase inhibitors R406 and GS-9973 impair T cell functions and macrophage-mediated anti-tumor activity of rituximab in chronic lymphocytic leukemia patients" . Cancer Immunology, Immunotherapy 66, no. 4 (2017) : 461-473.
---------- MLA ----------
Colado, A., Almejún, M.B., Podaza, E., Risnik, D., Stanganelli, C., Elías, E.E., et al. "The kinase inhibitors R406 and GS-9973 impair T cell functions and macrophage-mediated anti-tumor activity of rituximab in chronic lymphocytic leukemia patients" . Cancer Immunology, Immunotherapy, vol. 66, no. 4, 2017, pp. 461-473.
---------- VANCOUVER ----------
Colado, A., Almejún, M.B., Podaza, E., Risnik, D., Stanganelli, C., Elías, E.E., et al. The kinase inhibitors R406 and GS-9973 impair T cell functions and macrophage-mediated anti-tumor activity of rituximab in chronic lymphocytic leukemia patients. Cancer Immunol. Immunother. 2017;66(4):461-473.