Dasatinib, a small-molecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation

Author:

Schade Andrew E.12,Schieven Gary L.3,Townsend Robert3,Jankowska Anna M.1,Susulic Vojkan3,Zhang Rosemary3,Szpurka Hadrian1,Maciejewski Jaroslaw P.1

Affiliation:

1. Experimental Hematology and Hematopoiesis Section, Taussig Cancer Center and

2. Department of Clinical Pathology, Cleveland Clinic Foundation, OH; and

3. Immunology Drug Discovery, Bristol-Myers Squibb Research and Development, Princeton, NJ

Abstract

Abstract Dasatinib is an oral small molecule inhibitor of Abl and Src family tyrosine kinases (SFK), including p56Lck (Lck). Given the central importance of Lck in transmitting signals from the T-cell receptor (TCR) signaling complex and the potent ability of dasatinib to inhibit Lck activity, we hypothesized this agent could provide a novel route of immunomodulation via targeted inhibition of antigen-induced signaling. Herein, we show that dasatinib inhibits TCR-mediated signal transduction, cellular proliferation, cytokine production, and in vivo T-cell responses. However, dasatinib-mediated inhibition does not induce apoptosis because the effect is reversible or may be overcome by signals bypassing the TCR, such as phorbol ester. Signal transduction and proliferative responses via IL-2 remain essentially unperturbed, suggesting that dasatinib displays specificity for TCR signaling. In addition, dasatinib combined with cyclosporine A or rapamycin led to a much more potent inhibition of T-cell activation, suggesting that targeted inhibition of Lck could be a useful adjunct for enhanced immunomodulation. In combination with currently available immunomodulatory agents, SFK inhibition could potentially increase immunomodulatory efficacy while minimizing toxicity of individual agents.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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