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Blood, 1 December 2004, Vol. 104, No. 12, pp. 3754-3757.
Prepublished online as a Blood First Edition Paper on August 10, 2004; DOI 10.1182/blood-2004-06-2189.
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NEOPLASIA
Brief report
Sensitivity of oncogenic KIT mutants to the kinase inhibitors MLN518 and PD180970
Amie S. Corbin,
Ian J. Griswold,
Paul La Rosée,
Kevin W. H. Yee,
Michael C. Heinrich,
Corinne L. Reimer,
Brian J. Druker, and
Michael W. N. Deininger
From the Oregon Health and Science University Cancer Institute, Portland; Howard Hughes Medical Institute; III. Medizinische Universitätsklinik, Fakultät für klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany; Portland Veterans Administration Medical Center, Oregon Health and Science University Cancer Institute; and Millennium Pharmaceuticals, Cambridge, MA.
Oncogenic mutations of the receptor tyrosine kinase KIT occur in gastrointestinal stromal tumors (GISTs), some cases of acute myelogenous leukemia (AML), and systemic mastocytosis (SM). GISTs commonly contain mutations of the KIT juxtamembrane region while SM and AML harbor active site KIT mutations. Imatinib, which potently inhibits juxtamembrane mutants, is effective for the treatment of GISTs but has no activity against active site mutants. We analyzed the inhibitory potential of 2 small molecule inhibitors, MLN518 and PD180970, against different classes of KIT mutants. Both compounds inhibit the growth of cell lines expressing juxtamembrane mutant KIT. MLN518 additionally targets active site mutant cell lines, inhibiting cell proliferation, KIT, and signal transducer and activator of transcription-3 (Stat3) phosphorylation and inducing apoptosis at concentrations that may be clinically achievable. As phase 1 clinical trials of MLN518 in AML have shown little toxicity, our data suggest MLN518 is a promising candidate for the treatment of SM or AML with KIT mutations.
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