Sensitivity of oncogenic KIT mutants to the kinase inhibitors MLN518 and PD180970

Amie S. Corbin, Ian J. Griswold, Paul La Rosée, Kevin Yee, Michael Heinrich, Corinne L. Reimer, Brian Druker, Michael W N Deininger

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66 Scopus citations

Abstract

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 analysed 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.

Original languageEnglish (US)
Pages (from-to)3754-3757
Number of pages4
JournalBlood
Volume104
Issue number12
DOIs
Publication statusPublished - Dec 1 2004
Externally publishedYes

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ASJC Scopus subject areas

  • Hematology

Cite this

Corbin, A. S., Griswold, I. J., La Rosée, P., Yee, K., Heinrich, M., Reimer, C. L., ... Deininger, M. W. N. (2004). Sensitivity of oncogenic KIT mutants to the kinase inhibitors MLN518 and PD180970. Blood, 104(12), 3754-3757. https://doi.org/10.1182/blood-2004-06-2189