A FLT3 tyrosine kinase inhibitor is selectively cytotoxic to acute myeloid leukemia blasts harboring FLT3 internal tandem duplication mutations

Abstract

Internal tandem duplication (ITD) mutations of the receptor tyrosine kinase FLT3 have been found in 20% to 30% of patients with acute myeloid leukemia (AML). These mutations constitutively activate the receptor and appear to be associated with a poor prognosis. Recent evidence that this constitutive activation is leukemogenic renders this receptor a potential target for specific therapy. In this study, dose-response cytotoxic assays were performed with AG1295, a tyrosine kinase inhibitor active against FLT3, on primary blasts from patients with AML. For each patient sample, the degree of cytotoxicity induced by AG1295 was compared to the response to cytosine arabinoside (Ara C) and correlated with the presence or absence of a FLT3/ITD mutation. AG1295 was specifically cytotoxic to AML blasts harboring FLT3/ITD mutations. The results suggest that these mutations contribute to the leukemic process and that the FLT3 receptor represents a therapeutic target in AML. (Blood. 2001;98:885-887)

FLT3: ITDoes matter in leukemia

“…Furthermore, AG1295 was selectively cytotoxic to primary AML blasts harboring FLT3/ITD mutations, a finding that further validates FLT3 as a therapeutic target. 139 Another compound, CEP-701, has been shown to inhibit very potently and more selectively FLT3 autophosphorylation in vitro and in vivo (IC 50 of 2-3 nM for FLT3 compared with an IC 50 of 4500 nM for KIT), and, like AG1295, is preferentially cytotoxic to leukemia cells harboring constitutively activated FLT3. 79 A number of additional small-molecule tyrosine kinase inhibitors with activity against FLT3 have now been identified (Table 5).…”

“…The first FLT3 inhibitors to be identified were the tyrphostins AG1295 and AG1296. 90,138,139 These compounds, originally characterized as PDGF-R inhibitors, 140 inhibit FLT3 autophosphorylation in vitro (each with an IC 50 of 300 nM), and are cytotoxic to FLT3-dependent cell lines at doses that correspond to the inhibition of FLT3 autophosphorylation. Furthermore, AG1295 was selectively cytotoxic to primary AML blasts harboring FLT3/ITD mutations, a finding that further validates FLT3 as a therapeutic target.…”

The emerging role of Wnt signaling in the pathogenesis of acute myeloid leukemia

“…Flt3-ITD mutations result in ligand-independent kinase activation mediating proliferation and survival, block of myeloid differentiation, as well as induction of leukemic transformation in hematopoietic progenitor cell lines and primary mouse bone marrow. 76,[105][106][107] The mechanisms of leukemic transformation through Flt3-ITD mutations are not fully understood. Genes that are differentially expressed upon expression of Flt3-ITD were identified in the myeloid progenitor cell line 32Dcl3.…”

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

“…Several trials combining TKI and conventional chemotherapy are ongoing in patients with newly diagnosed FLT3-mutant AML or in AML in relapse. [221][222][223][224][225][226][227][228][229] TKI may also target c-KIT mutations, although in such cases the exact location and nature of the mutation must be determined individually because specific inhibitors are active against particular c-KIT mutations. For example, cells carrying insertion/deletion in exon 8, ITD of exon 11 and 12 or substitutions at codon 822 are sensitive to imatinib, while D816 mutations confer a resistance to imatinib but can be targeted with other TKI such as midostaurin, nilotinib or dasatinib.…”