Effects of AMN107, a novel aminopyrimidine tyrosine kinase inhibitor, on human mast cells bearing wild-type or mutated codon 816 c-kit

Srdan Verstovsek, Cem Akin, Taghi Manshouri, Alfonso Quintás-Cardama, Ly Huynh, Paul Manley, Ayalew Tefferi, Jorge Cortes, Francis J. Giles, Hagop Kantarjian

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

Most adults with systemic mastocytosis (SM) carry an activating mutation in the codon 816 of c-kit. We investigated the activity of the new tyrosine kinase inhibitor AMN107 on c-kit mutated mast cell lines and bone marrow samples from patients with SM and compared it to that of imatinib mesylate, a tyrosine kinase inhibitor effective in some patients with SM. In HMC-1560 mast cells carrying wild-type codon 816 c-kit, AMN107 was very effective and as potent as imatinib in inhibiting cellular proliferation and inducing apoptosis (P < 0.0823). By contrast, in HMC-1560,816 cells bearing a c-kit mutation in codon 816, neither drug exerted a significant effect (P < 0.0015). AMN107 was also as effective as imatinib in inhibiting phosphorylation of c-kit in HMC-1560 cells. However, AMN107 had little effect on ex vivo survival of bone marrow mast cells with 816 c-kit mutation obtained from patients with SM. Based upon our results, AMN107 and imatinib are equipotent against mast cells with wild-type c-kit and those harboring the juxtamembrane D560G c-kit mutant but have no significant activity over the dose range tested against cells expressing the c-kit D816V mutant tyrosine kinase.

Original languageEnglish (US)
Pages (from-to)1365-1370
Number of pages6
JournalLeukemia Research
Volume30
Issue number11
DOIs
StatePublished - Nov 1 2006
Externally publishedYes

Keywords

  • AMN107
  • c-Kit kinase inhibitor
  • Imatinib
  • Mastocytosis

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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    Verstovsek, S., Akin, C., Manshouri, T., Quintás-Cardama, A., Huynh, L., Manley, P., Tefferi, A., Cortes, J., Giles, F. J., & Kantarjian, H. (2006). Effects of AMN107, a novel aminopyrimidine tyrosine kinase inhibitor, on human mast cells bearing wild-type or mutated codon 816 c-kit. Leukemia Research, 30(11), 1365-1370. https://doi.org/10.1016/j.leukres.2006.04.005