PURPOSE: The dual BCR-ABL/SRC kinase inhibitor dasatinib entered the clinic for 
the treatment of chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia. 
Because SRC kinases are known to play an important role in physiologic T-cell 
activation, we analyzed the immunobiological effects of dasatinib on T-cell 
function. The effect of dasatinib on multiple T-cell effector functions was 
examined at clinically relevant doses (1-100 nmol/L); the promiscuous tyrosine 
kinase inhibitor staurosporine was used as a comparator.
EXPERIMENTAL DESIGN: Purified human CD3+ cells and virus-specific CD8+ T cells 
from healthy blood donors were studied directly ex vivo; antigen-specific 
effects were confirmed in defined T-cell clones. Functional outcomes included 
cytokine production (interleukin-2, IFN gamma, and tumor necrosis factor alpha), 
degranulation (CD107a/b mobilization), activation (CD69 up-regulation), 
proliferation (carboxyfluorescein diacetate succinimidyl ester dilution), 
apoptosis/necrosis induction, and signal transduction.
RESULTS: Both dasatinib and staurosporine inhibited T-cell activation, 
proliferation, cytokine production, and degranulation in a dose-dependent 
manner. Mechanistically, this was mediated by the blockade of early signal 
transduction events and was not due to loss of T-cell viability. Overall, CD4+ T 
cells seemed to be more sensitive to these effects than CD8+ T cells, and naïve 
T cells more sensitive than memory T-cell subsets. The inhibitory effects of 
dasatinib were so profound that all T-cell effector functions were shut down at 
therapeutically relevant concentrations.
CONCLUSION: These findings indicate that caution is warranted with use of this 
drug in the clinical setting and provide a rationale to explore the potential of 
dasatinib as an immunosuppressant in the fields of transplantation and 
T-cell-driven autoimmune diseases.