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Blood. 2018 Oct 15. pii: blood-2018-08-872465. doi: 10.1182/blood-2018-08-872465. [Epub ahead of print]

Targeted inhibition of PI3Kα/δ is synergistic with BCL-2 blockade in genetically defined subtypes of DLBCL.

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Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States.
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, United States.
Department of Immunology, Medical University of Warsaw, Warsaw, Poland.
Department of Hematology and Oncology, University Medical Center, Gottingen, Germany.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States;


Inhibition of the B-cell receptor (BCR) signaling pathway is a promising treatment strategy in multiple B-cell malignancies. However, the role of BCR blockade in diffuse large B-cell lymphoma (DLBCL) remains undefined. We recently characterized primary DLBCL subsets with distinct genetic bases for perturbed BCR/PI3K signaling and dysregulated BCL-2 expression. Herein, we explore the activity of PI3K inhibitors and BCL-2 blockade in a panel of functionally and genetically characterized DLBCL cell line models. A PI3K inhibitor with predominant α/δ activity, copanlisib, exhibited the highest cytotoxicity in all BCR-dependent DLBCLs. The pro-apoptotic effect of copanlisib was associated with DLBCL subtype-specific dysregulated expression of BCL-2 family members including HRK and its anti-apoptotic partner BCL-xL, BFL-1, MCL-1 and BIM. Using functional BH3 profiling, we found that the cytotoxic activity of copanlisib was primarily mediated through BCL-xL and MCL-1-dependent mechanisms that might complement BCL-2 blockade. For these reasons, we evaluated single agent activity of venetoclax in the DLBCLs and identified a subset with limited sensitivity to BCL-2 blockade despite having genetic bases of BCL-2 dysregulation. As these were largely BCR-dependent DLBCLs, we hypothesized that combined inhibition of PI3Kα/δ and BCL-2 would perturb BCR-dependent and BCL2-mediated survival pathways. Indeed, we observed synergistic activity of copanlisib/venetoclax in BCR-dependent DLBCLs with genetic bases for BCL-2 dysregulation in vitro and confirmed these findings in a xenograft model. These results provide pre-clinical evidence for the rational combination of PI3Kα/δ and BCL-2 blockade in genetically defined DLBCLs.

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