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Blood, 1 July 2006, Vol. 108, No. 1, pp. 286-291. Prepublished online as a Blood First Edition Paper on January 24, 2006; DOI 10.1182/blood-2005-10-3969. This Article Full Text (PDF) All Versions of this Article: 2005-10-3969v1 108/1/286    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Shah, N. P Articles by Akin, C. Search for Related Content PubMed PubMed Citation Articles by Shah, N. P Articles by Akin, C. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 4, 2005 Accepted January 13, 2006 Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in the majority of patients with systemic mastocytosis Neil P Shah, Francis Y Lee, Roger Luo, Yibin Jiang, Marjolein Donker, and Cem Akin* Division of Hematology/Oncology, The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA Bristol-Myers Squibb Oncology, Princeton, NJ, USA Division of Allergy & Immunology, University of Michigan School of Medicine, Ann Arbor, MI, USA Division of Allergy & Immunology, University of Michigan School of Medicine, Ann Arbor, MI, USA; University Medical Center Groningen, Groningen, The Netherlands * Corresponding author; email: cemakin{at}umich.edu. Systemic mastocytosis is associated with an activating mutation in the KIT oncoprotein (KITD816V) which results in auto-phosphorylation 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 mastocytosis 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 is not predicted to impair binding of KIT by dasatinib. Based upon our results, further evalutation of dasatinib for the treatment of systemic mastocytosis in clinical trials are warranted. Moreover, dasatinib may be of clinical utility in other disease settings driven by activating KIT mutations. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. R. Bandi, C. Brandts, M. Rensinghoff, R. Grundler, L. Tickenbrock, G. Kohler, J. Duyster, W. E. Berdel, C. Muller-Tidow, H. Serve, et al. 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