Activities of SYK and PLC?2 Predict Apoptotic Response of CLL Cells to SRC Tyrosine Kinase Inhibitor Dasatinib

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Activities of SYK and PLC?2 Predict Apoptotic Response of CLL Cells to SRC

Tyrosine Kinase Inhibitor Dasatinib

Zibo Song1, Pin Lu1, R. Furman2, P. Leonard2, 2,

Tyrell2, Francis Y. Lee3, M. Knowles1, Morton 2 and Y. Lynn Wang1

Author Affiliations

1.. Authors' Affiliations:1Department of Pathology and Laboratory Medicine;

2Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical

College, New York, New York; and 3Oncology Drug Discovery, Bristol-Myers Squibb

Research and Development, Princeton, New Jersey

1.. Corresponding Author:

Y. Lynn Wang, Department of Pathology and Laboratory Medicine, Weill Cornell

Medical College, 1300 York Avenue, New York, NY 10065. Phone: 212-746-6485; Fax:

212-746-8345; E-mail: lyw2001@....

Abstract

Purpose: B-cell receptor signaling plays an important role in the pathogenesis

of chronic lymphocytic leukemia (CLL). However, blocking B-cell receptor

signaling with dasatinib, an inhibitor of SRC kinase, produced variable results

in preclinical and clinical studies. We aim to define the molecular mechanisms

underlying the differential dasatinib sensitivity and to uncover more effective

therapeutic targets in CLL.

Experimental Design: Fresh CLL B cells were treated with dasatinib, and cell

viability was followed. The CLL cases were then divided into good and poor

responders. The cellular response was correlated with the activities of B-cell

receptor signaling molecules, as well as with molecular and cytogenetic

prognostic factors.

Results: Among 50 CLL cases, dasatinib treatment reduced cell viability by 2% to

90%, with an average reduction of 47% on day 4 of culture. The drug induced CLL

cell death through the intrinsic apoptotic pathway mediated by reactive oxygen

species. Unexpectedly, phosphorylation of SRC family kinases was inhibited by

dasatinib in good, as well as poor, responders. As opposed to SRC family

kinases, activities of two downstream molecules, SYK and phospholipase C?2,

correlate well with the apoptotic response of CLL cells to dasatinib.

Conclusions: Thus, SYK inhibition predicts cellular response to dasatinib. SYK,

together with phospholipase C?2, may serve as potential biomarkers to predict

dasatinib therapeutic response in patients. From the pathogenic perspective, our

study suggests the existence of alternative mechanisms or pathways that activate

SYK, independent of SRC kinase activities. The study further implicates that SYK

might serve as a more effective therapeutic target in CLL treatment. Clin Cancer

Res; 16(2); 587-99

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