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.
abstract: 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.
authors.affiliation: 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, 1425, Buenos Aires, Argentina.
authors.forename: Ana
authors.initials: A
authors.lastname: Colado
authors.affiliation: 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, 1425, Buenos Aires, Argentina.|Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: María Belén
authors.initials: MB
authors.lastname: Almejún
authors.affiliation: 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, 1425, Buenos Aires, Argentina.
authors.forename: Enrique
authors.initials: E
authors.lastname: Podaza
authors.affiliation: 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, 1425, Buenos Aires, Argentina.
authors.forename: Denise
authors.initials: D
authors.lastname: Risnik
authors.affiliation: Servicio de Patología Molecular, Instituto de Investigaciones Hematológicas-ANM, Buenos Aires, Argentina.
authors.forename: Carmen
authors.initials: C
authors.lastname: Stanganelli
authors.affiliation: 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, 1425, Buenos Aires, Argentina.
authors.forename: Esteban Enrique
authors.initials: EE
authors.lastname: Elías
authors.affiliation: Laboratorio de Genética de Neoplasias Linfoides, IMEX-CONICET-ANM, Buenos Aires, Argentina.
authors.forename: Patricia
authors.initials: P
authors.lastname: Dos Santos
authors.affiliation: Laboratorio de Genética de Neoplasias Linfoides, IMEX-CONICET-ANM, Buenos Aires, Argentina.
authors.forename: Irma
authors.initials: I
authors.lastname: Slavutsky
authors.affiliation: Departamento de Hematología, Sanatorio Julio Méndez, Buenos Aires, Argentina.
authors.forename: Horacio
authors.initials: H
authors.lastname: Fernández Grecco
authors.affiliation: Departamento de Hematología, Sanatorio Julio Méndez, Buenos Aires, Argentina.
authors.forename: María
authors.initials: M
authors.lastname: Cabrejo
authors.affiliation: Sección de Hematología, Hospital General de Agudos Dr. Teodoro Álvarez, Buenos Aires, Argentina.
authors.forename: Raimundo Fernando
authors.initials: RF
authors.lastname: Bezares
authors.affiliation: 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, 1425, Buenos Aires, Argentina.|Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Mirta
authors.initials: M
authors.lastname: Giordano
authors.affiliation: 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, 1425, Buenos Aires, Argentina.|Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Romina
authors.initials: R
authors.lastname: Gamberale
authors.affiliation: 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, 1425, Buenos Aires, Argentina. mercedesborge@hotmail.com.|Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina. mercedesborge@hotmail.com.
authors.forename: Mercedes
authors.identifier: http://orcid.org/0000-0002-1256-2364
authors.initials: M
authors.lastname: Borge
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D008213:Lymphocyte Activation / Q000187:drug effects; D008264:Macrophages / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010078:Oxazines / Q000494:pharmacology*; D010587:Phagocytosis / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D000069283:Rituximab / Q000494:pharmacology; D000072377:Syk Kinase / Q000037:antagonists & inhibitors*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism*; D009025:Morpholines
chemical_list: D007191:Indazoles; D010078:Oxazines; D011719:Pyrazines; D011725:Pyridines; D011948:Receptors, Antigen, T-Cell; D000069283:Rituximab; D000072377:Syk Kinase; D051746:ZAP-70 Protein-Tyrosine Kinase; C000589391:6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo(1,2-a)pyrazin-8-amine; D009025:Morpholines; C510788:N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine
keywords: BCR-associated kinase inhibitors; Chronic lymphocytic leukemia; GS-9973; R406; Syk inhibitors