1. Academic Validation
  2. The combination of FLT3 and SYK kinase inhibitors is toxic to leukaemia cells with CBL mutations

The combination of FLT3 and SYK kinase inhibitors is toxic to leukaemia cells with CBL mutations

  • J Cell Mol Med. 2020 Feb;24(3):2145-2156. doi: 10.1111/jcmm.14820.
Ellen Weisberg 1 2 Chengcheng Meng 1 Abigail E Case 1 Hong L Tiv 3 Prafulla C Gokhale 3 Anthia A Toure 1 Sara Buhrlage 4 Xiaoxi Liu 4 Jinhua Wang 5 Nathanael Gray 5 Richard Stone 1 2 Sophia Adamia 1 2 Eric Winer 1 2 Martin Sattler 1 2 James D Griffin 1 2
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 2 Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • 3 Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 4 Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 5 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
Abstract

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.

Keywords

AML; FLT3; leukaemia; mutant CBL; tyrosine kinase.

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