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Blood, 1 June 2002, Vol. 99, No. 11, pp. 3885-3891
PLENARY PAPER
A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to
leukemia cells in vitro and in vivo
Mark Levis,
Jeffrey Allebach,
Kam-Fai Tse,
Rui Zheng,
Brenda R. Baldwin,
B. Douglas Smith,
Susan Jones-Bolin,
Bruce Ruggeri,
Craig Dionne, and
Donald Small
From Johns Hopkins University School of Medicine,
Departments of Oncology and Pediatrics, Baltimore, MD; and Cephalon,
West Chester, PA.
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.

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