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 language | English (US) |
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Pages (from-to) | 1365-1370 |
Number of pages | 6 |
Journal | Leukemia Research |
Volume | 30 |
Issue number | 11 |
DOIs | |
State | Published - Nov 2006 |
Externally published | Yes |
Keywords
- AMN107
- Imatinib
- Mastocytosis
- c-Kit kinase inhibitor
ASJC Scopus subject areas
- Hematology
- Oncology
- Cancer Research