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Blood. 2018 May 24;131(21):2345-2356. doi: 10.1182/blood-2017-10-809210. Epub 2018 Mar 22.

Pan-SRC kinase inhibition blocks B-cell receptor oncogenic signaling in non-Hodgkin lymphoma.

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Swiss Institute for Experimental Cancer Research, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland.
Molecular Modeling Group, Swiss Institute of Bioinformatics, Quartier Sorge, Bâtiment Génopode, Lausanne, Switzerland; and.
Department of Fundamental Oncology, Ludwig Lausanne Branch, University of Lausanne, Epalinges, Switzerland.


In diffuse large B-cell lymphoma (DLBCL), activation of the B-cell receptor (BCR) promotes multiple oncogenic signals, which are essential for tumor proliferation. Inhibition of the Bruton's tyrosine kinase (BTK), a BCR downstream target, is therapeutically effective only in a subgroup of patients with DLBCL. Here, we used lymphoma cells isolated from patients with DLBCL to measure the effects of targeted therapies on BCR signaling and to anticipate response. In lymphomas resistant to BTK inhibition, we show that blocking BTK activity enhanced tumor dependencies from alternative oncogenic signals downstream of the BCR, converging on MYC upregulation. To completely ablate the activity of the BCR, we genetically and pharmacologically repressed the activity of the SRC kinases LYN, FYN, and BLK, which are responsible for the propagation of the BCR signal. Inhibition of these kinases strongly reduced tumor growth in xenografts and cell lines derived from patients with DLBCL independent of their molecular subtype, advancing the possibility to be relevant therapeutic targets in broad and diverse groups of DLBCL patients.

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