C-kit mutations determine dasatinib mechanism of action in HMC-1 neoplastic mast cells: dasatinib differently regulates PKCδ translocation in HMC-1⁵⁶⁰ and HMC-1^560,816 cell lines

Abstract

Purpose: The second generation of tyrosine kinase inhibitors is a group of compounds that inhibit c-kit receptor activity and therefore widely used in the treatment of mastocytosis. In this research, the relationship between the mechanism of action of tyrosine kinase inhibitors and protein kinase C is investigated in HMC-1⁵⁶⁰ or HMC-1^560,816 cell lines.

Results: From all the tyrosine kinase inhibitors tested, nilotinib is the compound that has the highest cytotoxic effect against HMC-1⁵⁶⁰ mast cell line, while midostaurin is the most potent in HMC-1^560,816. Moreover, an increase on histamine release is observed after protein kinase C activation either in HMC-1⁵⁶⁰ or HMC-1^560,816 cells. Furthermore, dasatinib increases histamine release in both mast cell lines, which could be related with the secondary reactions previously described in dasatinib-treated patients. Dasatinib also induces Ca²⁺-dependent protein kinase C isoforms translocation from the cytosol to the membrane, whereas protein kinase Cδ is translocated from the cytosol to the nucleus in the HMC-1^560,816 cell line, but not in HMC-1⁵⁶⁰ cells.

Conclusion: Results obtained demonstrate that dasatinib induces an important cytotoxic effect in both HMC-1 cell lines and differently regulates protein kinase Cδ in HMC-1⁵⁶⁰ and HMC-1^560,816 cells. Finally, our results confirm that PKCδ is an essential target for dasatinib.

• C-kit
• dasatinib
• HMC-1
• PKC
• PMA

Declaration of interest

The authors report no declarations of interest.

The research leading to these results has received funding from the following FEDER cofunded-grants: CDTI and Technological Funds, supported by Ministerio de Economía y Competitividad [AGL2012-40185-CO2-01, AGL2014-58210-R] and Consellería de Cultura, Educación e Ordenación Universitaria [GRC2013-016] and through Axencia Galega de Innovación, Spain [ITC-20133020 SINTOX]; CDTI under ISIP Programme, Spain [IDI-20130304 APTAFOOD]; the European Union’s Seventh Framework Programme managed by Research Executive Agency (REA) (FP7/2007-2013) under grant agreement [312184 PHARMASEA]. Araceli Tobío is the recipient of a Fundación Juana de Vega Fellowship (Spain).