Effects of MLN518, a dual FLT3 and KIT inhibitor, on normal and malignant hematopoiesis.
Internal tandem duplications (ITDs) of the FMS-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase are found in approximately 30% of patients with acute myelogenous leukemia (AML) and are associated with a poor prognosis. FLT3 ITD mutations result in constitutive kinase activation and are thought to be pathogenetically relevant, implicating FLT3 as a plausible therapeutic target. MLN518 (formerly CT53518) is a small molecule inhibitor of the FLT3, KIT, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases with significant activity in murine models of FLT3 ITD-positive leukemia. Given the importance of FLT3 and KIT for normal hematopoietic progenitor cells, we analyzed the effect of MLN518 on murine hematopoiesis under steady-state conditions, after chemotherapy-induced myelosuppression, and during bone marrow transplantation. In these assays, we show that MLN518 has mild toxicity toward normal hematopoiesis at concentrations that are effective in treating FLT3 ITD-positive leukemia in mice. We also demonstrate that MLN518 preferentially inhibits the growth of blast colonies from FLT3 ITD-positive compared with ITD-negative patients with AML, at concentrations that do not significantly affect colony formation by normal human progenitor cells. In analogy to imatinib mesylate in BCR-ABL-positive acute leukemia, MLN518-induced remissions may not be durable. Our studies provide the basis for integrating this compound into chemotherapy and transplantation protocols.
Griswold
Ian J
IJ
Howard Hughes Medical Institute, Oregon Health and Science University Cancer Institute, Portland 97239, USA.
Shen
Lei J
LJ
La Rosée
Paul
P
Demehri
Shadmehr
S
Heinrich
Michael C
MC
Braziel
Rita M
RM
McGreevey
Laura
L
Haley
Andrea D
AD
Giese
Neill
N
Druker
Brian J
BJ
Deininger
Michael W N
MW
D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology; D016026:Bone Marrow Transplantation; D002453:Cell Cycle / Q000187:drug effects; D003114:Colony-Forming Units Assay; D005260:Female; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects*; D011799:Quinazolines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D020080:Tandem Repeat Sequences; D014184:Transplantation, Homologous; D051941:fms-Like Tyrosine Kinase 3
D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; C464670:tandutinib; C497970:FLT3 protein, human; C497971:Flt3 protein, mouse; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3