title: Effect of tyrosine kinase inhibitor STI571 on the kinase activity of wild-type and various mutated c-kit receptors found in mast cell neoplasms.
abstract: Systemic mastocytosis (SM) is a rare disease caused by an abnormal mast cell accumulation in various tissues. Two classes of constitutive activating c-kit mutations are found in SM. The most frequent class occurs in the catalytic pocket coding region with substitutions at codon 816 and the other in the intracellular juxtamembrane coding region. Therefore, kinase inhibitors that block mutated c-kit activity might be used as therapeutic agents in SM. Here, we show that STI571 inhibits both wild-type and juxtamembrane mutant c-kit kinase activity, but has no effect on the activity of the D816 V mutant. Accordingly, STI571 selectively decreases the survival of normal mast cell and of mast cell lines either with juxtamembrane c-kit mutations, but not that of tumoral mast cell from patient with SM or of mast cell lines with the D816 V mutation. Therefore, STI571 is not a good candidate to treat SM and specific kinase inhibitors should be designed to inhibit constitutive activating mutations at codon 816.
authors.affiliation: CNRS UMR 8603, Hôpital Necker, Université René Descartes, Paris, France.
authors.forename: Yael
authors.initials: Y
authors.lastname: Zermati
authors.forename: Paulo
authors.initials: P
authors.lastname: De Sepulveda
authors.forename: Frederic
authors.initials: F
authors.lastname: Féger
authors.forename: Sebastion
authors.initials: S
authors.lastname: Létard
authors.forename: Joelle
authors.initials: J
authors.lastname: Kersual
authors.forename: Nathalie
authors.initials: N
authors.lastname: Castéran
authors.forename: Guy
authors.initials: G
authors.lastname: Gorochov
authors.forename: Michel
authors.initials: M
authors.lastname: Dy
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribadeau Dumas
authors.forename: Karim
authors.initials: K
authors.lastname: Dorgham
authors.forename: Christophe
authors.initials: C
authors.lastname: Parizot
authors.forename: Yann
authors.initials: Y
authors.lastname: Bieche
authors.forename: Michel
authors.initials: M
authors.lastname: Vidaud
authors.forename: Olivier
authors.initials: O
authors.lastname: Lortholary
authors.forename: Michel
authors.initials: M
authors.lastname: Arock
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
authors.forename: Patrice
authors.initials: P
authors.lastname: Dubreuil
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D020134:Catalytic Domain / Q000235:genetics; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D000068877:Imatinib Mesylate; D034721:Mastocytosis, Systemic / Q000188:drug therapy* / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects* / Q000235:genetics*; D011743:Pyrimidines / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit