The Tyrosine Kinase Inhibitor Dasatinib Enhances Glucocorticoid-Induced Apoptosis and Sensitizes Chronic Lymphocytic Leukemia Cells to Dexamethasone.

Abstract 4811

Glucocorticoid hormones are frequently used as part of front-line therapy to treat lymphoid neoplasms. However, relative to acute lymphoblastic leukemia and many types of B cell lymphoma, chronic lymphocytic leukemia (CLL) cells are intrinsically resistant to glucocorticoids and the mechanism governing this resistance has not been fully investigated. Here we report that that the Src inhibitor dasatinib enhances glucocorticoid-induced apoptosis in lymphoid cells and sensitizes primary CLL cells to dexamethasone. This finding evolved from the observation that the Src kinase Lck was downregulated by dexamethasone in glucocorticoid sensitive T cells in order to suppress immunoreceptor activation and signaling. In contrast, aberrantly expressed Lck was not downregulated by dexamethasone in CLL cells. However, inhibition of Lck phosphorylation by dasatinib significantly enhanced cell killing to nanomolar concentrations of dexamethasone. Collectively, these data indicate that dasatinib sensitizes primary CLL cells to glucocorticoids, and thus, the combination of these agents may have therapeutic efficacy in patients with aggressive or refractory CLL.