Open AccessThe combination of FLT3 and SYK kinase inhibitors is toxic to leukaemia cells with CBL mutations
Author(s) -
Weisberg Ellen,
Meng Chengcheng,
Case Abigail E.,
Tiv Hong L.,
Gokhale Prafulla C.,
Toure Anthia A.,
Buhrlage Sara,
Liu Xiaoxi,
Wang Jinhua,
Gray Nathanael,
Stone Richard,
Adamia Sophia,
Winer Eric,
Sattler Martin,
Griffin James D.
Publication year - 2020
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.14820
Subject(s) - syk , midostaurin , cancer research , tyrosine kinase , nilotinib , myeloid leukemia , ubiquitin ligase , fms like tyrosine kinase 3 , mutant , biology , leukemia , chemistry , mutation , signal transduction , microbiology and biotechnology , ubiquitin , imatinib , immunology , biochemistry , gene
Mutations in the E3 ubiquitin ligase CBL, found in several myeloid neoplasms, lead to decreased ubiquitin ligase activity. In murine systems, these mutations are associated with cytokine‐independent proliferation, thought to result from the activation of hematopoietic growth receptors, including FLT3 and KIT. Using cell lines and primary patient cells, we compared the activity of a panel of FLT3 inhibitors currently being used or tested in AML patients and also evaluated the effects of inhibition of the non‐receptor tyrosine kinase, SYK. We show that FLT3 inhibitors ranging from promiscuous to highly targeted are potent inhibitors of growth of leukaemia cells expressing mutant CBL in vitro , and we demonstrate in vivo efficacy of midostaurin using mouse models of mutant CBL. Potentiation of effects of targeted FLT3 inhibition by SYK inhibition has been demonstrated in models of mutant FLT3‐positive AML and AML characterized by hyperactivated SYK. Here, we show that targeted SYK inhibition similarly enhances the effects of midostaurin and other FLT3 inhibitors against mutant CBL‐positive leukaemia. Taken together, our results support the notion that mutant CBL‐expressing myeloid leukaemias are highly sensitive to available FLT3 inhibitors and that this effect can be significantly augmented by optimum inhibition of SYK kinase.