Crenolanib is a type I tyrosine kinase inhibitor that inhibits mutant KIT D816 isoforms prevalent in systemic mastocytosis and core binding factor leukemia
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Kerstin Maria Kampa-Schittenhelm1, Julia Frey1, Lara A. Haeusser1, Barbara Illing1, Ashly A. Pavlovsky2, Gunnar Blumenstock3 and Marcus Matthias Schittenhelm1
1University Hospital Tübingen, Department of Oncology, Hematology, Rheumatology, Clinical Immunology and Pulmology, Tübingen, Germany
2Arog Pharmaceuticals, Inc., Dallas, Texas, USA
3Institute of Clinical Epidemiology and Applied Biometry, Eberhard Karls University Tübingen, Tübingen, Germany
Kerstin Maria Kampa-Schittenhelm, email: [email protected]
Keywords: crenolanib, KIT, D816V, mastocytosis, leukemia
Received: November 15, 2016 Accepted: July 20, 2017 Published: August 07, 2017
Activating D816 mutations of the class III receptor tyrosine kinase KIT are associated with the majority of patients with systemic mastocytosis (SM), but also core binding factor (CBF) AML, making KIT 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 KIT 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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