FLT3 (fms-related tyrosine kinase/Flk2/ Stk-2) is a receptor tyrosine kinase (RTK) primarily expressed on hematopoietic cells. In blasts from acute myelogenous leukemia (AML) patients, 2 classes of FLT3 activating mutations have been identified: internal tandem duplication (ITD) mutations in the juxtamembrane domain (25%-30% of patients) and point mutations in the kinase domain activation loop (7%-8% of patients). FLT3-ITD mutations are the most common molecular defect identified in AML and have been shown to be an independent prognostic factor for decreased survival. FLT3-ITD is therefore an attractive molecular target for therapy. SU11248 is a recently described selective inhibitor with selectivity for split kinase domain RTKs, including platelet-derived growth factor receptors, vascular endothelial growth factor receptors, and KIT. We show that SU11248 also has potent activity against wild-type FLT3 (

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IntroductionThe receptor tyrosine kinase (RTK) c-kit is essential for the development of normal hematopoietic cells and has been proposed to play a functional role in acute myeloid leukemia (AML). 1,2 c-Kit is a member of the class III family of RTKs, characterized by an extracellular ligand binding region containing 5 immunoglobulin repeats, a hydrophobic transmembrane domain, and an intracellular kinase domain split by an insert. 3 Binding of the c-kit ligand, stem cell factor (SCF), initiates a signal transduction cascade that includes receptor autophosphorylation and subsequent phosphorylation on numerous intracellular substrates. c-Kit and its ligand play a pivotal role in normal hematopoiesis, as evidenced by naturally occurring murine mutations at the Sl locus, which encodes SCF, as well as in the c-kit receptor itself. These mutations result in varying degrees of macrocytic anemia and a loss of mast cells in addition to deficiencies in gametogenesis and melanogenesis. [4][5][6] In addition to its role in normal hematopoiesis, c-kit is expressed in leukemic blasts in approximately 60% to 80% of AML patients, as assessed by surface immunostaining using antibodies specific to c-kit or by expression of c-kit messenger RNA. 1,7,8 Supporting a functional role for c-kit in AML, increased tyrosine phosphorylation of the receptor, as well as a proliferative response upon SCF stimulation, has been demonstrated in leukemic blasts in most AML cases that were c-kit ϩ . 1,2 The proliferative response to SCF has been shown to be synergistic with granulocytemacrophage colony-stimulating factor (GM-CSF) or interleukin (IL)-3, both of which are known to promote the growth of leukemic cells in vitro.SU5416 and SU6668 are small-molecule inhibitors of RTKs such as Flk-1/KDR that have structural and sequence similarity to c-kit. SU5416 is a more selective and potent inhibitor of the Flk-1/KDR receptor; in contrast, SU6668 exhibits a broader inhibitory target profile, with effects on platelet-derived growth factor (PDGF) receptor and fibroblast growth factor (FGF) receptor in addition to Flk-1/KDR. 9,10 Both compounds have been shown to exhibit selectivity with respect to other tyrosine kinases, for example, with inhibitory concentration of 50% (IC 50 ) above 10 M for epidermal growth factor (EGF) receptor, Src, Met,10 In cell-based and preclinical animal models, both compounds have also been shown to exhibit antiangiogenic properties. SU5416 inhibits vascular endothelial growth factor (VEGF)-induced and SU6668 VEGF-and FGF-induced proliferation of human umbilical vein endothelial cells in culture; however, neither compound potently inhibits the growth of tumor cells grown in culture. 9,10 In addition, both compounds inhibit the growth of a variety of tumor cells grown as subcutaneous xenografts in athymic mice; furthermore, SU6668 has been shown to regress established xenograft tumors in mice. 9,10 Intravital fluoresence videomicroscopy in mouse tumor xenograft models has demonstrated that SU5416 and SU6668 also inhibit tumor...

Members of the Wnt gene family are proposed to function in both normal development and differentiation as well as in mammary tumorigenesis. To understand the function of Wnt proteins in these two processes, we present here a biochemical characterization of seven Wnt family members. For these studies, AtT-20 cells, a neuroendocrine cell line previously shown to efficiently process and secrete Wnt-1, was transfected with expression vectors encoding Wnt family members. All of the newly characterized Wnt proteins are glycosylated, secreted proteins that are tightly associated with the cell surface or extracellular matrix. We have also identified native Wnt proteins in retinoic acid-treated P19 embryonal carcinoma cells, and they exhibit the same biochemical characteristics as the recombinant proteins. These data suggest that Wnt family members function in cell to cell signaling in a fashion similar to Wnt-1.

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