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Lymphoma

Tyrosine kinase inhibition in diffuse large B-cell lymphoma: molecular basis for antitumor activity and drug resistance of dasatinib

Leukemia volume 22, pages 1755–1766 (2008)Cite this article

Abstract

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 G1-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 Cγ2 (PLCγ2), 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 PLCγ2 as biomarkers to predict dasatinib therapeutic response in prospective clinical trials.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA

    C Yang, P Lu, A Chadburn, D M Knowles & Y L Wang

  2. Oncology Drug Discovery, Bristol-Myers Squibb Research and Development, Princeton, NJ, USA

    F Y Lee

  3. Department of Medicine, Division of Hematology/Oncology, Weill Cornell Medical College, New York, NY, USA

    J C Barrientos & J P Leonard

  4. Department of Pathology, Mount Sinai School of Medicine, New York, NY, USA

    F Ye & D Zhang

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  1. C Yang
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Correspondence to Y L Wang.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Yang, C., Lu, P., Lee, F. et al. Tyrosine kinase inhibition in diffuse large B-cell lymphoma: molecular basis for antitumor activity and drug resistance of dasatinib. Leukemia 22, 1755–1766 (2008). https://doi.org/10.1038/leu.2008.163

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