title: FLT3 and KIT mutated pediatric acute myeloid leukemia (AML) samples are sensitive in vitro to the tyrosine kinase inhibitor SU11657.
abstract: New treatment strategies to improve the outcome of pediatric acute myeloid leukemia (AML) are required as 40% of children diagnosed with AML do not survive. Around 30% of pediatric AML patients harbour a mutation in the tyrosine kinases FLT3 (+/-20%) or KIT (+/-10%). In this study we investigated whether pediatric AML samples (N=61) were sensitive to the tyrosine kinase inhibitor SU11657 (similar to the clinically available drug sunitinib) in vitro, and whether sensitivity was related to expression of, and mutations in, FLT3 and KIT. Overall, SU11657 showed only moderate cytotoxicity. A FLT3 mutation was detected in 35% and a KIT mutation in 8% of the samples. FLT3 and KIT mutated samples were significantly more sensitive to SU11657 than WT KIT and FLT3 samples. Samples without KIT or FLT3 mutations, but with a high wild-type (WT) KIT expression were significantly more sensitive to SU11657 than samples with low KIT expression. Further clinical evaluation of SU11657 and sunitinib combined with chemotherapy would be of interest. Inclusion in clinical trials should not be restricted to patients with FLT3 or KIT mutations.
authors.affiliation: Pediatric Oncology and Hematology, VU University Medical Center, Amsterdam, The Netherlands. bf.goemans@vumc.nl
authors.forename: Bianca F
authors.initials: BF
authors.lastname: Goemans
authors.forename: Christian M
authors.initials: CM
authors.lastname: Zwaan
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Cloos
authors.forename: Desiree
authors.initials: D
authors.lastname: de Lange
authors.forename: Anne H
authors.initials: AH
authors.lastname: Loonen
authors.forename: Dirk
authors.initials: D
authors.lastname: Reinhardt
authors.forename: Karel
authors.initials: K
authors.lastname: Hählen
authors.forename: Brenda E S
authors.initials: BE
authors.lastname: Gibson
authors.forename: Ursula
authors.initials: U
authors.lastname: Creutzig
authors.forename: Gertjan J L
authors.initials: GJ
authors.lastname: Kaspers
mesh_terms: D000293:Adolescent; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D009154:Mutation; D009930:Organic Chemicals / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D009930:Organic Chemicals; C474557:SU 11657; C497970:FLT3 protein, human; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3