Inhibitors of Bcl-2 and Bruton\u2019s tyrosine kinase synergize to abrogate diffuse large B-cell lymphoma growth in vitro and in orthotopic xenotransplantation models

Katrin Bertram,Vineet Dalal,Alexandar Tzankov,Christophe Boudesco,Kristin Stirm,Peter John Leary,Thorsten Zenz,Jonas Fullin,Anne Müller

doi:10.1038/s41375-021-01470-4

Abstract

Numerous targeted therapies have been developed for diffuse large B-cell lymphoma, but the results of late-stage clinical trials were mostly disappointing and have led to very few new regulatory approvals. Here, we use single and combinatorial drug response profiling to show that the combined inhibition of the anti-apoptotic protein Bcl-2 and of the tyrosine kinase BTK with the small molecules venetoclax and ibrutinib efficiently kills DLBCL cells in vitro. High Bcl-2 expression due to either BCL2 amplifications or translocations, in conjunction with chronic active BCR signaling accurately predict responses to dual Bcl-2/BTK inhibition. Orthotopic xenotransplantation and patient-derived xenograft models confirm that the combinatorial is superior to single-agent treatment in reducing the lymphoma burden. Combinatorial treatment further efficiently overcomes both primary and acquired resistance to venetoclax, which we could link to reduced expression of the Bcl-2 family members Bcl-XL and Bcl-2A1 under ibrutinib. We found in a Swiss DLBCL cohort that ~15% of patients are projected to respond to the venetoclax/ibrutinib combination based on their high Bcl-2 expression and nuclear NF-κB localization. Our data show that drug sensitivities exposed by drug response profiling can be attributed to specific mutational signatures and immunohistochemical biomarkers, and point to combined Bcl-2/BTK inhibition as a promising therapeutic strategy in DLBCL.

Highlights

INTRODUCTION Diffuse largeB-cell lymphoma (DLBCL) is an aggressive malignancy of the mature B-cell that may arise de novo in both lymphoid and non-lymphoid organs
The refined stratification based on genetic abnormalities has led to the differentiation of two subtypes of ABCDLBCL, of which one is characterized by MYD88 and CD79B mutations and BCL2 gains, extranodal manifestations, a genetic signature of aberrant somatic hypermutation driven by activation-induced cytidine deaminase activity and a dismal prognosis; the other subtype is characterized by NOTCH2 and BCL6 mutations and structural aberrations, respectively, and the associated downstream transcriptional signatures, a presumably extrafollicular origin more reminiscent of marginal zone lymphoma, and a comparatively superior prognosis [10, 11]
Drug response profiling identifies specific sensitivities of Diffuse largeB-cell lymphoma (DLBCL) cell lines that can be confirmed by genetic ablation of the drug target We systematically assessed the sensitivities of 19 lymphoma cell lines to 126 FDA-approved compounds, which were chosen based on their activity on pathways that are known to be deregulated in hematopoietic malignancies (Supplementary Table 1)

Summary

Introduction

INTRODUCTION Diffuse largeB-cell lymphoma (DLBCL) is an aggressive malignancy of the mature B-cell that may arise de novo in both lymphoid and non-lymphoid organs. 4 Fig. 2 The level of Bcl-2 expression determines venetoclax sensitivity of DLBCL cell lines in vitro and in vivo.

Results

Conclusion