The kinase inhibitors R406 and GS-9973 impair T cell functions and macrophage-mediated anti-tumor activity of rituximab in chronic lymphocytic leukemia patients. Academic Article uri icon

Overview

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.

publication date

  • December 23, 2016

Research

keywords

  • Indazoles
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Macrophages
  • Oxazines
  • Pyrazines
  • Pyridines
  • Syk Kinase
  • T-Lymphocytes
  • ZAP-70 Protein-Tyrosine Kinase

Identity

Scopus Document Identifier

  • 85007173764

Digital Object Identifier (DOI)

  • 10.1007/s00262-016-1946-y

PubMed ID

  • 28011996

Additional Document Info

volume

  • 66

issue

  • 4