Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies

Activating mutations of the activation loop of KIT are associated with certain human neoplasms, including the majority of patients with systemic mast cell disorders, as well as cases of seminoma, acute myelogenous leukemia (AML), and gastrointestinal stromal tumors (GISTs). The small-molecule tyrosi...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2006, Vol.66 (1), p.473-481
Main Authors: SCHITTENHELM, Marcus M, SHIRAGA, Sharon, SCHROEDER, Arin, CORBIN, Amie S, GRIFFITH, Diana, LEE, Francis Y, BOKEMEYER, Carsten, DEININGER, Michael W. N, DRUKER, Brian J, HEINRICH, Michael C
Format: Article
Language:English
Subjects:
Amino Acid Substitution
Animals
Antineoplastic agents
Benzamides
Biological and medical sciences
Cell Growth Processes - drug effects
Cell Survival - drug effects
CHO Cells
Cricetinae
Dasatinib
General aspects
Hematologic Neoplasms - drug therapy
Hematologic Neoplasms - enzymology
Humans
Imatinib Mesylate
Isoenzymes - metabolism
MAP Kinase Signaling System
Medical sciences
Mice
Mutation
Pharmacology. Drug treatments
Phosphorylation
Piperazines - pharmacology
Protein Kinase Inhibitors - pharmacology
Protein Structure, Tertiary
Proto-Oncogene Proteins c-abl - antagonists & inhibitors
Proto-Oncogene Proteins c-kit - metabolism
Pyrimidines - pharmacology
src-Family Kinases - antagonists & inhibitors
Thiazoles - pharmacology
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Summary:Activating mutations of the activation loop of KIT are associated with certain human neoplasms, including the majority of patients with systemic mast cell disorders, as well as cases of seminoma, acute myelogenous leukemia (AML), and gastrointestinal stromal tumors (GISTs). The small-molecule tyrosine kinase inhibitor imatinib mesylate is a potent inhibitor of wild-type (WT) KIT and certain mutant KIT isoforms and has become the standard of care for treating patients with metastatic GIST. However, KIT activation loop mutations involving codon D816 that are typically found in AML, systemic mastocytosis, and seminoma are insensitive to imatinib mesylate (IC50 > 5-10 micromol/L), and acquired KIT activation loop mutations can be associated with imatinib mesylate resistance in GIST. Dasatinib (formerly BMS-354825) is a small-molecule, ATP-competitive inhibitor of SRC and ABL tyrosine kinases with potency in the low nanomolar range. Some small-molecule SRC/ABL inhibitors also have potency against WT KIT kinase. Therefore, we hypothesized that dasatinib might inhibit the kinase activity of both WT and mutant KIT isoforms. We report herein that dasatinib potently inhibits WT KIT and juxtamembrane domain mutant KIT autophosphorylation and KIT-dependent activation of downstream pathways important for cell viability and cell survival, such as Ras/mitogen-activated protein kinase, phosphoinositide 3-kinase/Akt, and Janus-activated kinase/signal transducers and activators of transcription. Furthermore, dasatinib is a potent inhibitor of imatinib-resistant KIT activation loop mutants and induces apoptosis in mast cell and leukemic cell lines expressing these mutations (potency against KIT D816Y >> D816F > D816V). Our studies suggest that dasatinib may have clinical efficacy against human neoplasms that are associated with gain-of-function KIT mutations.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-05-2050