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Barry EV, Clark JJ, Cools J, Roesel J, Gilliland DG. Blood.
2007 Dec 15;110(13):4476-9
Uniform sensitivity of FLT3 activation loop mutants to the
tyrosine kinase inhibitor midostaurin.
Barry EV, Clark JJ, Cools J, Roesel J, Gilliland DG.
Dana-Farber Cancer Institute, Department of Pediatric
Oncology, Boston, MA 02115, USA.
elly_barry@dfci.harvard.edu
Small molecule inhibitors that target fms-like tyrosine
kinase 3 (FLT3)-activating mutations have potential in the
treatment of leukemias. However, certain mutations can
simultaneously activate the tyrosine kinase, and confer
resistance to small molecule inhibitors. We therefore tested the
sensitivity of 8 FLT3 activation loop mutants to midostaurin.
Each mutant conferred IL-3 factor-independent proliferation to
Ba/F3 cells, and each resulted in the constitutive activation of
FLT3 and its targets, signal transducer and activator of
transcription 5 (STAT5) and extracellular stimuli-responsive
kinase (ERK). For each mutant tested, midostaurin inhibited cell
growth and phosphorylation of FLT3, STAT5, and ERK. In contrast,
midostaruin did not inhibit Ba/F3 cells stably transduced with
FLT3-internal tandem duplications containing a G697R mutation
that confers resistance to midostaurin, demonstrating that
midostaurin inhibition of FLT3 activation loop mutants was not
due to off-target effects. We conclude that midostaurin is a
potent inhibitor of a spectrum of FLT3 activation loop
mutations, and that acute myeloid leukemia patients with such
mutations are potential candidates for clinical trials involving
midostaurin.
PMID: 17827387 |
