ABSTRACT
Constitutively activated tyrosine kinases have been investigated for decades now for their role in the pathogenesis of different cancers. Tyrosine kinases, in particular, seem to be important in the development of hematologic malignancies, especially myeloid leukemias. FMS-like tyrosine kinase 3 (FLT3)/internal tandem duplication mutations have a prevalence of 10% to 17% in pediatric cute myeloid leukemia (AML), and FLT3 kinase domain mutations occur in another 7% of cases. AML samples harboring activating mutations consistently respond in vitro more dramatically than wild-type samples to FLT3 inhibition. FLT3 mutations occur much less frequently in childhood acute lymphoid leukemia than in adult or pediatric AML. The signaling properties of an FLT3 receptor with an ITD mutation differ from those of the wild-type receptor in a manner that clearly contributes to the process of leukemogenesis. CEP-701 is the only FLT3 inhibitor for which preclinical data are available specifically for pediatric AML.
