title: 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.
abstract: 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.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Oregon Health and Science University, Portland, USA.
authors.forename: Marcus M
authors.initials: MM
authors.lastname: Schittenhelm
authors.forename: Sharon
authors.initials: S
authors.lastname: Shiraga
authors.forename: Arin
authors.initials: A
authors.lastname: Schroeder
authors.forename: Amie S
authors.initials: AS
authors.lastname: Corbin
authors.forename: Diana
authors.initials: D
authors.lastname: Griffith
authors.forename: Francis Y
authors.initials: FY
authors.lastname: Lee
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
authors.forename: Michael W N
authors.initials: MW
authors.lastname: Deininger
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.forename: Michael C
authors.initials: MC
authors.lastname: Heinrich
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001549:Benzamides; D016466:CHO Cells; D048708:Cell Growth Processes / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D000069439:Dasatinib; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D006801:Humans; D000068877:Imatinib Mesylate; D007527:Isoenzymes / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D001549:Benzamides; D007527:Isoenzymes; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases; D000069439:Dasatinib