Dasatinib inhibits B cell receptor signalling in chronic lymphocytic leukaemia but novel combination approaches are required to overcome additional pro-survival microenvironmental signals

McCaig, A. M., Cosimo, E., Leach, M. T. and Michie, A. M. (2011) Dasatinib inhibits B cell receptor signalling in chronic lymphocytic leukaemia but novel combination approaches are required to overcome additional pro-survival microenvironmental signals. British Journal of Haematology, 153(2), pp. 199-211. (doi: 10.1111/j.1365-2141.2010.08507.x)

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Publisher's URL: http://dx.doi.org/10.1111/j.1365-2141.2010.08507.x

Abstract

As antigenic stimulation of the B cell antigen receptor (BCR) is key to chronic lymphocytic leukaemia (CLL) pathogenesis, targeting dysregulated kinases involved in BCR signalling is an attractive therapeutic approach. We studied the effects of the Src/c-Abl tyrosine kinase inhibitor dasatinib on BCR signal transduction in CLL cells. Treatment of CLL cells with 100 nmol/l dasatinib induced apoptosis by an average reduction in viability of 33•7% at 48 h, with dasatinib sensitivity correlating with inhibition of Syk<sup>Y348</sup> phosphorylation. Dasatinib inhibited calcium flux, phosphatidylinositol-3-kinase and mitogen-activated protein kinase activation following BCR crosslinking, and blocked the Mcl-1-dependent increase in CLL cell survival on prolonged BCR stimulation. However, the pro-apoptotic effect of dasatinib was abrogated by stromal cell contact alone or in the presence of CD154 and interleukin (IL)-4 (CD154L/IL-4 system). Whilst dasatinib retained the ability to sensitize CLL cells in stromal co-culture to both fludarabine and chlorambucil, the addition of CD154 and IL-4 rendered cells resistant to these drug combinations. We demonstrate that the HSP90 inhibitor 17-DMAG exhibited synergy with dasatinibin vitro, and moreover, induced apoptosis of CLL cells in the CD154L/IL-4 system. Our data provide evidence that dasatinib would be most clinically effective in combination with agents able to target antigen-independent microenvironmental signals.<p></p>

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Michie, Dr Alison and Mccaig, Dr Alison and Cosimo, Dr Emilio
Authors: McCaig, A. M., Cosimo, E., Leach, M. T., and Michie, A. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:British Journal of Haematology
Publisher:Blackwell Publishing
ISSN:0007-1048
ISSN (Online):1365-2141
Published Online:24 February 2011
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
471842Developing a novel therapeutic approach in chronic lymphocytic leukaemiaAlison McCaigMedical Research Council (MRC)G0701354Institute of Cancer Sciences