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Lymphoma

Inhibition of SYK or BTK augments venetoclax sensitivity in SHP1-negative/BCL-2-positive diffuse large B-cell lymphoma

Leukemia volume 33, pages 2416–2428 (2019)Cite this article

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Abstract

The BCL-2 inhibitor venetoclax has only limited activity in DLBCL despite frequent BCL-2 overexpression. Since constitutive activation of the B cell receptor (BCR) pathway has been reported in both ABC and GCB DLBCL, we investigated whether targeting SYK or BTK will increase sensitivity of DLBCL cells to venetoclax. We report that pharmacological inhibition of SYK or BTK synergistically enhances venetoclax sensitivity in BCL-2-positive DLBCL cell lines with an activated BCR pathway in vitro and in a xenograft model in vivo, despite the only modest direct cytotoxic effect. We further show that these sensitizing effects are associated with inhibition of the downstream PI3K/AKT pathway and changes in the expression of MCL-1, BIM, and HRK. In addition, we show that BCR-dependent GCB DLBCL cells are characterized by deficiency of the phosphatase SHP1, a key negative regulator of the BCR pathway. Re-expression of SHP1 in GCB DBLCL cells reduces SYK, BLNK, and GSK3 phosphorylation and induces corresponding changes in MCL1, BIM, and HRK expression. Together, these findings suggest that SHP1 deficiency is responsible for the constitutive activation of the BCR pathway in GCB DLBCL and identify SHP1 and BCL-2 as potential predictive markers for response to treatment with a venetoclax/BCR inhibitor combination.

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Acknowledgements

This work was supported by grants from the Italian Association for Cancer Research (project no. AIRC IG2016 Id.19236), the ERA-NET TRANSCAN-2 program JTC 2014–project FIRE-CLL, the Horizon 2020 Programme (project 692180-STREAM-H2020-TWINN-2015), the Swedish Cancer Society, the Swedish Research Council, Uppsala University, Uppsala University Hospital, Lion’s Cancer Research Foundation, Borgström’s foundation and Selander’s Foundation.

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  1. Molecular Hematology, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy

    Binu K. Sasi, Claudio Martines, Elena Xerxa, Fabiola Porro, Hilal Kalkan, Rosa Fazio, Sven Turkalj, Engin Bojnik & Dimitar G. Efremov

  2. Department of Immunology, Medical University of Warsaw, Warsaw, Poland

    Beata Pyrzynska, Joanna Stachura, Abdessamad Zerrouqi, Małgorzata Bobrowicz & Magdalena Winiarska

  3. Institute of Oncology Research, Bellinzona, Switzerland

    Valdemar Priebe & Francesco Bertoni

  4. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden

    Larry Mansouri

  5. Dept. of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden

    Richard Rosenquist

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  1. Binu K. Sasi
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Contributions

BKS and DGE designed the study. BKS, CM, EX, FP, HK, RF, ST, EB, BP, JS, AZ, and MB performed the experiments. MW provided primary material and expert advice. VP and FB performed the bioinformatic analysis. LM and RR provided patient specimens and associated clinicopathologic data. BKS and DGE wrote the manuscript. All authors reviewed the manuscript.

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Correspondence to Dimitar G. Efremov.

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Sasi, B.K., Martines, C., Xerxa, E. et al. Inhibition of SYK or BTK augments venetoclax sensitivity in SHP1-negative/BCL-2-positive diffuse large B-cell lymphoma. Leukemia 33, 2416–2428 (2019). https://doi.org/10.1038/s41375-019-0442-8

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