title: Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis.
abstract: Mastocytosis is associated with an activating mutation in the KIT oncoprotein (KITD816V) that results in autophosphorylation of the KIT receptor in a ligand-independent manner. This mutation is inherently resistant to imatinib and, to date, there remains no effective curative therapy for systemic mastocytosis associated with KITD816V. Dasatinib (BMS-354825) is a novel orally bioavailable SRC/ABL inhibitor that has activity against multiple imatinib-resistant BCR-ABL isoforms in vitro that is presently showing considerable promise in early-phase clinical trials of chronic myeloid leukemia (CML). Pharmacokinetic analysis suggests that high nanomolar concentrations of dasatinib can be achieved safely in humans. In this study, we demonstrate significant inhibitory activity of dasatinib against both wild-type KIT and the KITD816V mutation in the nanomolar range in in vitro and cell-based kinase assays. Additionally, dasatinib leads to growth inhibition of a KITD816V-harboring human masto-cytosis cell line. Significantly, dasatinib selectively kills primary neoplastic bone marrow mast cells from patients with systemic mastocytosis while sparing other hematopoietic cells. Computer modeling suggests that the KITD816V mutation destabilizes the inactive conformation of the KIT activation loop to which imatinib binds, but it is not predicted to impair binding of KIT by dasatinib. Based upon our results, further evaluation of dasatinib for the treatment of systemic masto-cytosis in clinical trials is warranted. Moreover, dasatinib may be of clinical utility in other disease settings driven by activating KIT mutations.
authors.affiliation: Division of Hematology/Oncology, The David Geffen School of Medicine at University of California-Los Angeles (UCLA, CA, USA.
authors.forename: Neil P
authors.initials: NP
authors.lastname: Shah
authors.forename: Francis Y
authors.initials: FY
authors.lastname: Lee
authors.forename: Roger
authors.initials: R
authors.lastname: Luo
authors.forename: Yibin
authors.initials: Y
authors.lastname: Jiang
authors.forename: Marjolein
authors.initials: M
authors.lastname: Donker
authors.forename: Cem
authors.initials: C
authors.lastname: Akin
mesh_terms: D000818:Animals; D001549:Benzamides; D001665:Binding Sites; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D008024:Ligands; D034721:Mastocytosis, Systemic / Q000235:genetics*; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry / Q000187:drug effects*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001549:Benzamides; D008024:Ligands; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D000069439:Dasatinib