SYK Inhibition and Response Prediction in Diffuse Large B-Cell Lymphoma.
Lynn Y Wang, Shuhua Cheng, Hannah X Zhang, Rita Shaknovich, Zibo Song, Pin Lu, Anjali Pandey, Greg Coffey, Uma Sinha. Weill Cornell Medical College, New York, NY; Portola Pharmaceuticals Inc., South San Francisco, CA
Background: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Although about half of patients can be cured by the current immunochemotherapeutic regimen, novel agents are needed to further improve patient outcomes.
Design: B-cell receptor (BCR) signaling plays an important role in the pathogenesis of DLBCL. We hypothesized that inhibition of spleen tyrosine kinase (SYK), a key component of the BCR pathway, may have anti-lymphoma effects.
Results: In this study, using tissue microarray, we demonstrated for the first time that SYK is present and activated in primary human DLBCL tissues. A specific SYK inhibitor, PRT060318, blocked G1-S transition and caused cell cycle arrest in six sensitive DLBCL cell lines. This finding was confirmed by genetic reduction of SYK using siRNA. Among ten DLBCL cell lines, four were resistant to SYK inhibition. A detailed analysis of the BCR signaling pathways revealed that the activities of SYK, PLCg2, and AKT, as opposed to ERK1/2, were well correlated with cell line sensitivity to SYK inhibition, suggesting that these molecules are crucial in mediating the proliferation of lymphoma cells. Furthermore, the SYK inhibitor blocked BCR signaling in primary lymphoma cells.
Conclusions: Together, our findings not only show SYK inhibition 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 PLCg2 and AKT as biomarkers to predict therapeutic response in prospective clinical trials of SYK inhibitors.
Wednesday, March 2, 2011 1:00 PM
Poster Session VI # 211, Wednesday Afternoon