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Blood, 1 January 2007, Vol. 109, No. 1, pp. 315-322. Prepublished online as a Blood First Edition Paper on August 15, 2006; DOI 10.1182/blood-2006-04-013805. This Article Full Text (PDF) All Versions of this Article: blood-2006-04-013805v1 109/1/315    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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Pan, J. Articles by Verstovsek, S. Search for Related Content PubMed PubMed Citation Articles by Pan, J. Articles by Verstovsek, S. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 3, 2006 Accepted July 17, 2006 EXEL-0862, a novel tyrosine kinase inhibitor, induces apoptosis in vitro and ex vivo in human mast cells expressing the KIT D816V mutation Jingxuan Pan, Alfonso Quintas-Cardama, Hagop M Kantarjian, Cem Akin, Taghi Manshouri, Peter Lamb, Jorge Cortes, Ayalew Tefferi, Francis Giles, and Srdan Verstovsek* University of Texas M.D. Anderson Cancer Center, Houston, TX University of Texas M. D. Anderson Cancer Center, Houston, TX University of Michigan, Ann Arbor, MI Exelixis, Inc., South San Francisco, CA UT MD Anderson Cancer Center, Houston, TX Division of Hematology, Mayo Clinic College of Medicine, Rochester, MN * Corresponding author; email: sverstov{at}mdanderson.org. Gain-of-function mutations of the receptor tyrosine kinase KIT play a key role in the pathogenesis of systemic mastocytosis (SM), gastrointestinal stromal tumors (GIST) and some cases of acute myeloid leukemia (AML). Whereas KIT juxtamembrane domain mutations seen in most GIST cases are highly sensitive to imatinib, the kinase activation loop mutant D816V, frequently encountered in SM, hampers the binding ability of imatinib. We investigated the inhibitory activity of the novel tyrosine kinase inhibitor EXEL-0862 against two subclones of HMC-1 (human mast leukemia) cells, HMC-1.1 harboring the juxtamembrane domain mutation V560G, and HMC-1.2 carrying both V560G and the activation loop mutation D816V encountered in more than 80% of SM cases. EXEL-0862 inhibited the phosphorylation of KIT in a dose-dependent manner and decreased cell proliferation in both mast cell lines with higher activity against HMC-1.2 cells. Second, phosphorylation of KIT-dependent signals transducer and activator of transcription-3 (STAT3) and -5 (STAT5) was abrogated upon exposure to nanomolar EXEL-0862 concentrations. In addition, EXEL-0862 induced a time- and dose-dependent proapoptotic effect in both mast cell lines and caused a significant reduction in mast cell content in bone marrow samples from patients with SM harboring D816V as well as from those without D816V mutation. We conclude that EXEL-0862 is active against KIT activation loop mutants and is a promising candidate for the treatment of patients with SM and other KIT-driven malignancies harboring active site mutations. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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