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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.
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NEOPLASIA
EXEL-0862, a novel tyrosine kinase inhibitor, induces apoptosis in vitro and ex vivo in human mast cells expressing the KIT D816V mutation
Jingxuan Pan1,
Alfonso Quintás-Cardama1,
Hagop M. Kantarjian1,
Cem Akin2,
Taghi Manshouri1,
Peter Lamb3,
Jorge E. Cortes1,
Ayalew Tefferi4,
Francis J. Giles1, and
Srdan Verstovsek1,
1 The University of Texas M. D. Anderson Cancer Center, Houston, TX;
2 University of Michigan, Ann Arbor, MI;
3 Exelixis, San Francisco, CA;
4 Division of Hematology, Mayo Clinic College of Medicine, Rochester, MN.
Gain-of-function mutations of the receptor tyrosine kinase KIT play a key role in the pathogenesis of systemic mastocytosis (SM), gastrointestinal stromal tumors (GISTs), and some cases of acute myeloid leukemia (AML). Whereas KIT juxtamembrane domain mutations seen in most patients with GIST 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 2 subclones of human mast cell line-1 (HMC-1)—HMC-1.1, harboring the juxtamembrane domain mutation V560G, and HMC-1.2, carrying V560G and the activation loop mutation D816V, found in more than 80% of patients with SM. 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. The phosphorylation of KIT-dependent signal transducer and activator of transcription-3 (STAT3) and STAT5 was abrogated upon exposure to nanomolar concentrations of EXEL-0862. 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 and from those without the 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.
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