Effect of tyrosine kinase inhibitor STI571 on the kinase activity of wild-type and various mutated c-kit receptors found in mast cell neoplasms.
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.
Zermati
Yael
Y
CNRS UMR 8603, Hôpital Necker, Université René Descartes, Paris, France.
De Sepulveda
Paulo
P
Féger
Frederic
F
Létard
Sebastion
S
Kersual
Joelle
J
Castéran
Nathalie
N
Gorochov
Guy
G
Dy
Michel
M
Ribadeau Dumas
Antoni
A
Dorgham
Karim
K
Parizot
Christophe
C
Bieche
Yann
Y
Vidaud
Michel
M
Lortholary
Olivier
O
Arock
Michel
M
Hermine
Olivier
O
Dubreuil
Patrice
P
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
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