The effects of dasatinib on IgE receptor-dependent activation and histamine release in human basophils.

Dasatinib is a multitargeted drug that blocks several tyrosine kinases. Apart from its well-known antileukemic activity, the drug has attracted attention because of potential immunosuppressive and antiinflammatory effects. We report that dasatinib at 1 M completely blocks antiIgE‐induced histamine release in blood basophils in healthy donors, and allergeninduced release of histamine in sensitized individuals. In addition, dasatinib inhibited FcRI-mediated release of IL-4 and IgE-mediated up-regulation of CD13, CD63, CD164, and CD203c in basophils. The effects of dasatinib were dosedependent (IC50: 50-500 nM) and specific for FcRI activation in that the drug failed to inhibit C5a-induced or Ca-ionophore‐ induced histamine release. Interestingly, at lower concentrations, dasatinib even promoted FcRI-dependent histamine release in basophils in allergic subjects. In consecutive studies, dasatinib was found to interact with and block several FcRI downstream targets in basophils, including Btk. Correspondingly, FcRImediated histamine secretion in basophils was markedly reduced in Btk knockout mice and in a patient with Btk deficiency. However,theremaining“low-level”mediator secretion in Btk-deficient cells was fully blocked down again by 1 M dasatinib. Together, these data suggest that dasatinib inhibits FcRI-mediated activation of basophils through multiple signaling molecules including Btk. Dasatinib may be an interesting agent for immunologic disorders involving Btk-dependent responses or/and FcRI activation of basophils. (Blood. 2008;111:3097-3107)