Activities of SYK and PLCgamma2 predict apoptotic response of CLL cells to SRC tyrosine kinase inhibitor dasatinib.
OBJECTIVE
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.


METHODS
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 Cgamma2, correlate well with the apoptotic response of CLL cells to dasatinib.


CONCLUSIONS
Thus, SYK inhibition predicts cellular response to dasatinib. SYK, together with phospholipase Cgamma2, 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.
Song
Zibo
Z
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065, USA.
Lu
Pin
P
Furman
Richard R
RR
Leonard
John P
JP
Martin
Peter
P
Tyrell
Lauren
L
Lee
Francis Y
FY
Knowles
Daniel M
DM
Coleman
Morton
M
Wang
Y Lynn
YL
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D016923:Cell Death; D000069439:Dasatinib; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D051966:Phospholipase C gamma / Q000378:metabolism*; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D000072377:Syk Kinase; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D054316:Biomarkers, Pharmacological; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D019061:src-Family Kinases; D051966:Phospholipase C gamma; D000069439:Dasatinib