Tyrosine kinase inhibition in diffuse large B-cell lymphoma: molecular basis for antitumor activity and drug resistance of dasatinib.
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Although some patients can be cured by current therapies, novel agents are needed to further improve outcomes. We hypothesized that Src tyrosine kinase inhibition by dasatinib may have antilymphoma effects. Here, we demonstrate that dasatinib inhibits cell growth through G(1)-S blockage in five of seven DLBCL cell lines at clinically achievable concentrations. Compared to resting B cells, DLBCL has increased tyrosine phosphorylation activities. As expected, dasatinib inhibits phosphorylation of several Src family kinase members. However, this inhibition occurs in all cell lines regardless of their proliferative response to the drug. In contrast, the activity of two downstream signaling molecules, Syk and phospholipase Cgamma2 (PLCgamma2), are well correlated with cell line sensitivity to dasatinib, suggesting that these molecules are crucial in mediating the proliferation of activated lymphoma cells. Furthermore, dasatinib inhibits B-cell receptor signaling in primary lymphoma cells. Together, our findings not only show dasatinib as a potentially useful therapy for DLBCL but also provide insights into the pathogenesis of the lymphoma. The results further suggest the possibility of using Syk and PLCgamma2 as biomarkers to predict dasatinib therapeutic response in prospective clinical trials.
Yang
C
C
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
Lu
P
P
Lee
F Y
FY
Chadburn
A
A
Barrientos
J C
JC
Leonard
J P
JP
Ye
F
F
Zhang
D
D
Knowles
D M
DM
Wang
Y L
YL
D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007399:Interphase / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy*; D051966:Phospholipase C gamma / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D000072377:Syk Kinase; D013844:Thiazoles / Q000494:pharmacology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011947:Receptors, Antigen, B-Cell; D013844:Thiazoles; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D019061:src-Family Kinases; D051966:Phospholipase C gamma; D000069439:Dasatinib