TitleSYK inhibition and response prediction in diffuse large B-cell lymphoma.
Publication TypeJournal Article
Year of Publication2011
AuthorsCheng, Shuhua, Coffey Greg, X Zhang Hannah, Shaknovich Rita, Song Zibo, Lu Pin, Pandey Anjali, Melnick Ari M., Sinha Uma, and Y Wang Lynn
JournalBlood
Volume118
Issue24
Pagination6342-52
Date Published2011 Dec 08
ISSN1528-0020
KeywordsAntineoplastic Agents, Biomarkers, Cell Line, Tumor, Drug Resistance, Neoplasm, G1 Phase, Gene Expression Regulation, Neoplastic, Humans, Intracellular Signaling Peptides and Proteins, Lymph Nodes, Lymphoma, Large B-Cell, Diffuse, Molecular Targeted Therapy, Neoplasm Proteins, Phospholipase C gamma, Phosphorylation, Protein Kinase Inhibitors, Protein Processing, Post-Translational, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-akt, RNA Interference, RNA, Messenger, RNA, Small Interfering, Signal Transduction, Syk Kinase, Tumor Cells, Cultured
Abstract

<p>Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, and the role of SYK in its pathogenesis is not completely understood. Using tissue microarray, we demonstrated for the first time that SYK protein is activated in 27 of 61 (44%) primary human DLBCL tissues. Among DLBCL cell lines, 7 were sensitive and 3 were resistant to a highly specific SYK inhibitor, PRT060318. In sensitive DLBCL cells, SYK inhibition blocked the G(1)-S transition and caused cell-cycle arrest. This effect was reproduced by genetic reduction of SYK using siRNA. A detailed analysis of the BCR signaling pathways revealed that the consequence of SYK inhibition on PLCĪ³2 and AKT, as opposed to ERK1/2, was responsible for cell-cycle arrest. Genetic knock-down of these key molecules decelerated the proliferation of lymphoma cells. In addition, BCR signaling can be blocked by PRT060318 in primary lymphoma cells. Together, these findings provide insights into cellular pathways required for lymphoma cell growth and support the rationale for considering SYK inhibition as a potentially useful therapy for DLBCL. The results further suggest the possibility of using PLCĪ³2 and AKT as biomarkers to predict therapeutic response in prospective clinical trials of specific SYK inhibitors.</p>

DOI10.1182/blood-2011-02-333773
Alternate JournalBlood
PubMed ID22025527