title: A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo.
abstract: Constitutively activating internal tandem duplication (ITD) and point mutations of the receptor tyrosine kinase FLT3 are present in up to 41% of patients with acute myeloid leukemia (AML). These FLT3/ITD mutations are likely to be important because their presence is associated with a poor prognosis. Both types of mutations appear to activate the tyrosine kinase activity of FLT3. We describe here the identification and characterization of the indolocarbazole derivative CEP-701 as a FLT3 inhibitor. This drug potently and selectively inhibits autophosphorylation of wild-type and constitutively activated mutant FLT3 in vitro in FLT3/ITD-transfected cells and in human FLT3-expressing myeloid leukemia-derived cell lines. We demonstrate that CEP-701 induces a cytotoxic effect on cells in a dose-responsive fashion that parallels the inhibition of FLT3. STAT5 and ERK1/2, downstream targets of FLT3 in the signaling pathway, are inhibited in response to FLT3 inhibition. In primary leukemia blasts from AML patients harboring FLT3/ITD mutations, FLT3 is also inhibited, with an associated cytotoxic response. Finally, using a mouse model of FLT3/ITD leukemia, we demonstrate that the drug inhibits FLT3 phosphorylation in vivo and prolongs survival. These findings form the basis for a planned clinical trial of CEP-701 in patients with AML harboring FLT3- activating mutations.
authors: Johns Hopkins University School of Medicine, Department of Oncology, Baltimore, MD 21231-1000, USA.
authors: Mark
authors: M
authors: Levis
authors: Jeffrey
authors: J
authors: Allebach
authors: Kam-Fai
authors: KF
authors: Tse
authors: Rui
authors: R
authors: Zheng
authors: Brenda R
authors: BR
authors: Baldwin
authors: B Douglas
authors: BD
authors: Smith
authors: Susan
authors: S
authors: Jones-Bolin
authors: Bruce
authors: B
authors: Ruggeri
authors: Craig
authors: C
authors: Dionne
authors: Donald
authors: D
authors: Small
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000201:enzymology / Q000473:pathology; D002227:Carbazoles / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005663:Furans; D006801:Humans; D007211:Indoles; D007700:Kinetics; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D017354:Point Mutation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D051941:fms-Like Tyrosine Kinase 3
chemical_list: D000970:Antineoplastic Agents; D002227:Carbazoles; D004791:Enzyme Inhibitors; D005663:Furans; D007211:Indoles; D011518:Proto-Oncogene Proteins; C119379:lestaurtinib; C497970:FLT3 protein, human; C497971:Flt3 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases