Oncotarget

Research Papers:

Inhibition of BCR signaling using the Syk inhibitor TAK-659 prevents stroma-mediated signaling in chronic lymphocytic leukemia cells

Noelia Purroy, Júlia Carabia, Pau Abrisqueta, Leire Egia, Meritxell Aguiló, Cecilia Carpio, Carles Palacio, Marta Crespo _ and Francesc Bosch

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Oncotarget. 2017; 8:742-756. https://doi.org/10.18632/oncotarget.13557

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Abstract

Noelia Purroy1,*, Júlia Carabia1,*, Pau Abrisqueta1, Leire Egia1, Meritxell Aguiló1, Cecilia Carpio1, Carles Palacio1, Marta Crespo1,*, Francesc Bosch1,*

1Laboratory of Experimental Hematology, Department of Hematology, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain

*These authors contributed equally to this work

Correspondence to:

Marta Crespo, email: [email protected]

Keywords: CLL, Syk, microenvironment, TAK-659, BCR inhibitor

Received: May 18, 2016     Accepted: November 18, 2016     Published: November 24, 2016

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.


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