Introduction The FMS-like tyrosine kinase 3 (FLT3) is highly expressed in

Introduction The FMS-like tyrosine kinase 3 (FLT3) is highly expressed in acute leukemias. stem cells, as well as lymphoid and dendritic progenitor cells and cells of the immune system [4,5]. expression has also been detected in tissues 183552-38-7 other than early progenitor cells but to a much lesser degree [6]. The function of FLT3 can be defined by the activity of its ligand. Binding of FLT3 ligand (FL) to the receptor induces receptor dimerization which triggers receptor autophosphorylation [7], thereby, enabling the receptor to activate three major downstream pathways, transmission transducer and activator of transcription 5 (STAT5), RAS/MAPK and PI3K/AKT. These pathways contribute to 183552-38-7 cell differentiation, proliferation and survival [8-12]. FLT3 is also highly expressed in AML, B-lineage acute lymphoblastic leukemia (ALL) and to a lesser extent in T-lineage ALL [3,13,14]. Activating mutations including FLT3 are among the most common molecular abnormalities associated with AML and occur in 30% of adult patients with AML. The two most common activating mutations occur in the juxtamembrane domain name (JM) and the TKD. Disruption of the JM by internal tandem duplications (ITD) is usually detected in 20 C 25% of AML cases and at a low frequency in myelodysplastic syndrome [15,16]. These mutations are usually in frame and are 3 to 400 or more base pairs in length. Previously thought to be confined to the JM domain name, a recent analysis of 753 and mutations appear to 183552-38-7 confer a more favorable prognosis for patients with normal karyotype AML (NK-AML) [29], whereas mutations including in NK-AML are associated with shorter disease-free survival (DFS), remission period and OS [30-32]. In cases where and are both mutated, the favorable outcomes normally conferred by mutated are negated [29]. Additionally, several published reports describe high frequencies of mutations in acute promyelocytic leukemia (APL) and AML with a t(6;9)(p23; q34) translocation [30-35]. Consistent with previous reports, a recent retrospective analysis of mutations occur frequently in AML. Constitutive activation of is usually caused by ITD mutations in the JM region ((along with ligand activation via paracrine or autocrine signaling [54,55]. The impact on outcomes are unclear. Substantial desire for FLT3 as a therapeutic target has led to the development of several encouraging inhibitors of FLT3 that are in various stages of clinical development (Table 1) [56]. Table 1 FLT3 inhibitors in clinical studies for AML + genotype was performed. Inhibition of FLT3 phosphorylation was observed in 50% of FLT3-WT patients and in all of mutated patients. Substantial inhibition of FLT3 phosphorylation in > 50% of the patients was observed with sunitinib doses of 200 mg and higher. Drug-related adverse events occurred in 31% of the patients, but were limited to grade 1/2 diarrhea and nausea [71]. In another Phase I study, sunitinib was given to 15 relapsed or refractory AML patients at a starting dose of 50 mg/day for 4 weeks followed by a 2- or 1-week rest period [72]. Although short in duration, partial responses (PRs) or better were seen in all 4 patients harboring mutations as compared to 2 of 10 evaluable patients with with sunitinib and chemotherapy on inhibitor, has been studied in several preclinical studies in both solid and hematologic malignancies. Lestaurtinib has exhibited inhibition against the autophosphorylation of and [75,76]. inhibition with lestaurtinib resulted in improved survival in a mouse model [75]. Even though cytotoxicity of Mouse monoclonal to ApoE FLT3 inhibitors appears to be related to the inhibitory activity, there is great heterogeneity in responses. In general, it appears that blast cells with [76,77]. Furthermore, and studies showed synergistic cytotoxic effects in AML cell lines when lestaurtinib was given in combination with cytotoxic chemotherapy. Interestingly, this synergy was 183552-38-7 seen when.