Hopes for kinase inhibitors active against AML take FLT

The impressive activity of imatinib mesylate in patients with chronic-phase chronic myeloid leukemia (CML) has spurred the search for kinase inhibitors with similar efficacy in other hematologic malignancies. In acute myeloid leukemia (AML), considerable attention has focused on inhibitors of Fms-like tyrosine kinase 3 (FLT3), a member of the type III receptor tyrosine kinase family that also includes c-Kit and the platelet-derived growth factor receptor (reviewed in Gilliland and Griffin¹  and Levis and Small² ). In normal marrow, FLT3 is present on CD34⁺ and a small subset of CD34^– marrow cells, where it plays critical roles in the proliferation of pluripotent hematopoietic stem cells, development of B-cell progenitors, and production of dendritic cells.³  Soon after FLT3 was cloned, several groups reported that the vast majority of AMLs and acute lymphocytic leukemias express this receptor. Subsequent studies then demonstrated that FLT3 is a mutational target in AML, with small duplications of the juxtamembrane region in occurring 17% to 34% of cases and point mutations in the activation loop of the kinase occurring in another 7% to 14%.^1,2  Both types of mutations result in ligand-independent FLT3 phosphorylation, which is accompanied by constitutive activation of signal transduction pathways involving extracellular signal-related kinases (ERKs), phosphatidylinositol-3 kinase/Akt, and signal transducer and activator of transcription 5a (STAT5a).^1,2  In accord with the antiapoptotic effects of these pathways,⁴  the activating FLT3 mutations have emerged as independent predictors of particularly poor prognosis in children and adults with AML.^1,2 

Based on these observations, several semiselective FLT3 inhibitors have undergone extensive preclinical testing (reviewed in Sawyers⁵ ). These agents induce apoptosis in cell lines and clinical AML isolates that harbor activating FLT3 mutations. In addition, these agents exhibit promising activity in mice inoculated with leukemia cell lines transformed by mutant FLT3. Because cells lacking mutant FLT3 are relatively resistant to these agents in vitro, it has been suggested that these agents should be tested only in patients whose blasts contain FLT3 mutations.⁵ 

A new study by Zheng and colleagues (page 267) might prompt re-examination of this recommendation. Zheng and coworkers demonstrated that FLT3 ligand (FL), like FLT3, is expressed on the vast majority of primary AML isolates. Based on these results, Zheng and coworkers then examined the phosphorylation status of wild-type FLT3 in AML cell lines and clinical samples lacking activating mutations. Not only was constitutive FLT3 phosphorylation observed in the majority of clinical AML specimens expressing only wild-type FLT3, but the increased FLT3 phosphorylation that occurred during incubation in short-term cultures could also be prevented by coincubation with antibodies that block binding of FL to FLT3. These results raise the possibility that an autocrine or paracrine loop activates FLT3 in a sizable fraction of AML specimens that lack FLT3 mutations.

Like all good scientific studies, the present work leads to new questions. Does the putative FL/FLT3 loop lead to meaningful activation of the same antiapoptotic pathways activated by mutant FLT3? If so, what are the consequences of inhibiting the FL/FLT3 loop in these cells? Were the earlier studies showing lack of cytotoxicity of FLT3 inhibitors in vitro in AML lacking FLT3 mutations misleading because of their design or their small sample size? Alternatively, are cells with normal FLT3 less dependent on this receptor for survival signals? Finally, what can appropriately be expected of Flt3 inhibitors in clinical trials? Because Flt3 mutations are not themselves fully transforming,^1,2  might it be more realistic to think that that the inhibitors will modulate apoptotic pathways and enhance the efficacy of conventional antileukemic drugs rather than inducing remissions by themselves? Is it possible that FLT3 inhibitors might have broader applicability against acute leukemias than originally envisioned if used in this fashion? The next chapters of this unfolding tale are awaited with interest.