Pediatric AML primary samples with FLT3/ITD mutations are preferentially killed by FLT3 inhibition.
Pediatric acute myelogenous leukemia (AML) has a poor prognosis, and novel therapies are needed. The FLT3 tyrosine kinase represents a promising target in pediatric AML. FLT3 is constitutively activated either by an internal tandem duplication (ITD) or by a point mutation (PM) in 17% to 24% of pediatric AML cases. Autocrine stimulation of wild-type (WT) FLT3 by coexpressed FLT3 ligand (FL) occurs in many other cases. FLT3/ITD mutations confer a particularly poor prognosis in pediatric AML patients. Inhibitors of FLT3 are being tested in adult AML patients, with promising preliminary results. In this study, cytotoxicity and apoptosis assays were performed on 44 diagnostic pediatric AML blast samples (14 FLT3/WT, 15 FLT3/ITD, 15 FLT3/PM) using CEP-701, a potent and selective FLT3 inhibitor. Pronounced cytotoxicity and induction of apoptosis were observed in a higher percentage of FLT3/ITD samples (93%) than FLT3/PM (27%) or FLT3/WT (29%). The cytotoxicity was greatest in samples with a high FLT3/ITD mutant-to-wild-type allelic ratio. The addition of FL enhanced the survival and augmented the sensitivity to FLT3 inhibition for the CEP-701-responsive subset of FLT3/WT and FLT3/PM samples. Clinical testing of FLT3 inhibitors as molecularly targeted agents for the improvement of outcome of pediatric AML patients is warranted.
Brown
Patrick
P
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
Meshinchi
Soheil
S
Levis
Mark
M
Alonzo
Todd A
TA
Gerbing
Robert
R
Lange
Beverly
B
Arceci
Robert
R
Small
Donald
D
D000293:Adolescent; D017209:Apoptosis / Q000187:drug effects*; D002227:Carbazoles / Q000494:pharmacology* / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D005663:Furans; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D008024:Ligands; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D014407:Tumor Cells, Cultured; D051941:fms-Like Tyrosine Kinase 3
D002227:Carbazoles; D005663:Furans; D007211:Indoles; D008024:Ligands; D011518:Proto-Oncogene Proteins; C119379:lestaurtinib; C497970:FLT3 protein, human; 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