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

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

• Book ID: 104040163
• Publisher: Elsevier Science
• Year: 2006
• Tongue: English
• Weight: 422 KB
• Volume: 30
• Category: Article
• ISSN: 0145-2126
• DOI: 10.1016/j.leukres.2006.04.005

✦ Synopsis

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-1(560) 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-1(560,816) 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-1(560) 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.