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.

Signal transduction by several KIT juxtamembrane domain mutations

“…This may reflect some mechanistic or signaling differences not only between WT receptor activation and mutated receptor activation but also between two types of mutations. Interestingly, in this report we showed that JMD receptor appeared to be more sensitive to compounds reported to be active on the WT receptor, whereas these drugs are ineffective when assessed on KIT m814/h816 -mutated expressing cells (Ning et al, 2001;Frost et al, 2002;Zermati et al, 2003). These data are very encouraging in the perspective of treating GISTs with STi-571.…”

Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management

“…Demonstrates in vitro efficacy against wild-type KIT and certain transmembrane (F522C) and juxta-membrane (V560G) KIT mutants, but not the common kinase (D816V) domain mutants [45,[105][106][107]. Similarly, not all juxta-membrane mutations may be sensitive to IM (e.g., V559I) [108].…”

Cancer treatment with kinase inhibitors: what have we learnt from imatinib?

“…A syndrome related to histamine release may also occur. Imatinib inhibition of KIT phosphorylation in mast cell lines correlates with the inhibition of cellular proliferation (Zermati et al, 2003), suggesting that the cells are critically dependent on KIT activity. In systemic mastocytosis, the most common activating mutation in C-KIT D816V, occurs in the catalytic region of the enzyme, and also prevents binding of imatinib.…”

“…Most cases of mastocytosis are therefore resistant to imatinib. However, patients with mutations in the juxtamembrane region of the KIT molecule may retain in vitro sensitivity (Zermati et al, 2003) and durable clinical responses to imatinib in doses of 400 mg daily or less have been demonstrated .…”

“…The most common of these mutations (D816 V) shows no response to imatinib in vitro (Zermati et al, 2003), while the proliferation of normal mast cells containing wild-type C-KIT was significantly inhibited. It is thought that the D816V mutation interferes with the interaction of imatinib and its KIT binding site.…”