Crenolanib is a type I tyrosine kinase inhibitor that inhibits mutant KIT D816 isoforms prevalent in systemic mastocytosis and core binding factor leukemia
Activating D816 mutations of the class III receptor tyrosine kinase are associated with the majority of patients with systemic mastocytosis (SM), but also core binding factor (CBF) AML, making mutations attractive therapeutic targets for the treatment of these cancers. Crenolanib is a potent and sel...
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Published in | Oncotarget Vol. 8; no. 47; pp. 82897 - 82909 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Impact Journals LLC
10.10.2017
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Subjects | |
Online Access | Get full text |
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Summary: | Activating D816 mutations of the class III receptor tyrosine kinase
are associated with the majority of patients with systemic mastocytosis (SM), but also core binding factor (CBF) AML, making
mutations attractive therapeutic targets for the treatment of these cancers. Crenolanib is a potent and selective inhibitor of wild-type as well as mutant isoforms of the class III receptor tyrosine kinases FLT3 and PDGFRα/β. Notably, crenolanib inhibits constitutively active mutant-FLT3 isoforms resulting from amino acid substitutions of aspartic acid at codon 835, which is homologous to codon 816 in the
gene - suggesting sensitivity against mutant-KIT D816 isoforms as well. Here we demonstrate that crenolanib targets KIT D816 in SM and CBF AML models: crenolanib inhibits cellular proliferation and initiates apoptosis of mastocytosis cell lines expressing these mutations. Target-specificity was confirmed using an isogenic cell model. In addition, we demonstrate that KIT D816 mutations are targetable with clinically achievable doses of crenolanib. Further, a rationale to combine cladribine (2-CDA), the therapeutic standard in SM, with crenolanib is provided. In conclusion, we demonstrate that crenolanib is an inhibitor of mutant-KIT D816 isoforms at clinically achievable concentrations, and thus may be a potential treatment for SM and CBF AML as a monotherapy or in combination approaches. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1949-2553 1949-2553 |
DOI: | 10.18632/oncotarget.19970 |