論文 - 詳細
| RRC ID | 51952 |
|---|---|
| 著者 | Purroy N, Carabia J, Abrisqueta P, Egia L, Aguiló M, Carpio C, Palacio C, Crespo M, Bosch F. |
| タイトル | Inhibition of BCR signaling using the Syk inhibitor TAK-659 prevents stroma-mediated signaling in chronic lymphocytic leukemia cells. |
| ジャーナル | Oncotarget |
| Abstract |
Proliferation and survival of chronic lymphocytic leukemia (CLL) cells depend on microenvironmental signals coming from lymphoid organs. One of the key players involved in the crosstalk between CLL cells and the microenvironment is the B-cell receptor (BCR). Syk protein, a tyrosine kinase essential for BCR signaling, is therefore a rational candidate for targeted therapy in CLL. Against this background, we tested the efficacy of the highly specific Syk inhibitor TAK-659 in suppressing the favorable signaling derived from the microenvironment. To ex vivo mimic the microenvironment found in the proliferation centers, we co-cultured primary CLL cells with BM stromal cells (BMSC), CD40L and CpG ODN along with BCR stimulation. In this setting, TAK-659 inhibited the microenvironment-induced activation of Syk and downstream signaling molecules, without inhibiting the protein homologue ZAP-70 in T cells. Importantly, the pro-survival, proliferative, chemoresistant and activation effects promoted by the microenvironment were abrogated by TAK-659, which furthermore blocked CLL cell migration toward BMSC, CXCL12, and CXCL13. Combination of TAK-659 with other BCR inhibitors showed synergistic effect in inducing apoptosis, and the sequential addition of TAK-659 in ibrutinib-treated CLL cells induced significantly higher cytotoxicity. These findings provide a strong rationale for the clinical development of TAK-659 in CLL. |
| 巻・号 | 8(1) |
| ページ | 742-756 |
| 公開日 | 2017-1-3 |
| DOI | 10.18632/oncotarget.13557 |
| PII | 13557 |
| PMID | 27888629 |
| PMC | PMC5352193 |
| MeSH | Apoptosis / drug effects Biomarkers Burkitt Lymphoma / metabolism Cell Line, Tumor Cell Movement / drug effects Cell Proliferation / drug effects Cell Survival / drug effects Chemotaxis Coculture Techniques Drug Resistance, Neoplasm Humans Immunophenotyping Leukemia, Lymphocytic, Chronic, B-Cell / metabolism* Leukemia, Lymphocytic, Chronic, B-Cell / pathology Protein Kinase Inhibitors / pharmacology Pyrimidines / pharmacology* Pyrrolidinones / pharmacology* Receptors, Antigen, B-Cell / metabolism* Signal Transduction / drug effects* Stromal Cells / drug effects* Stromal Cells / metabolism* Syk Kinase / antagonists & inhibitors* Tumor Microenvironment / drug effects |
| IF | 5.168 |
| 引用数 | 10 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 6 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | UE6E7T-2(RCB2153) |