Inhibition of BCR signaling using the Syk inhibitor TAK-659 prevents stroma-mediated signaling in chronic lymphocytic leukemia cells.
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.
['Purroy|Noelia|N|', 'Carabia|Júlia|J|', 'Abrisqueta|Pau|P|', 'Egia|Leire|L|', 'Aguiló|Meritxell|M|', 'Carpio|Cecilia|C|', 'Palacio|Carles|C|', 'Crespo|Marta|M|', 'Bosch|Francesc|F|']
D017209:Apoptosis D015415:Biomarkers D002051:Burkitt Lymphoma D045744:Cell Line, Tumor D002465:Cell Movement D049109:Cell Proliferation D002470:Cell Survival D002633:Chemotaxis D018920:Coculture Techniques D019008:Drug Resistance, Neoplasm D006801:Humans D016130:Immunophenotyping D015451:Leukemia, Lymphocytic, Chronic, B-Cell D047428:Protein Kinase Inhibitors D011743:Pyrimidines D011760:Pyrrolidinones D011947:Receptors, Antigen, B-Cell D015398:Signal Transduction D017154:Stromal Cells D000072377:Syk Kinase D059016:Tumor Microenvironment
Syk TAK-659 CLL microenvironment BCR inhibitor