title: Uniform sensitivity of FLT3 activation loop mutants to the tyrosine kinase inhibitor midostaurin.
abstract: 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.
authors.affiliation: Dana-Farber Cancer Institute, Department of Pediatric Oncology, Boston, MA 02115, USA. elly_barry@dfci.harvard.edu
authors.forename: Elly V
authors.initials: EV
authors.lastname: Barry
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Clark
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
authors.forename: Johannes
authors.initials: J
authors.lastname: Roesel
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051379:Mice; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D050799:STAT5 Transcription Factor / Q000378:metabolism; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014161:Transduction, Genetic; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism