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.