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

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BlankDasatinib inhibits B cell receptor signalling in chronic lymphocytic

leukaemia but novel combination approaches are required to overcome additional

pro-survival microenvironmental signals.

AM McCaig, E Cosimo, MT Leach, and AM Michie

Br J Haematol, February 24, 2011; .

Institute of Cancer Sciences, College of Medical, Veterinary & Life Sciences,

University of Glasgow Department of Haematology, West of Scotland Cancer Centre,

Gartnavel General Hospital, Glasgow, UK.

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(Y348) 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 dasatinib in

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.

PMID: 21352196