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Lymphoma

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

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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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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