GSE171763
Inhibitors of Bcl-2 and Bruton's tyrosine kinase synergize to abrogate diffuse large B-cell lymphoma (DLBCL) growth
Methods: DLBCL cell lines RIVA, U-2932 and OCI-LY3 were treated in vitro with ibrutinib (Ibru) or dimethyl sulfoxide (DMSO). Additionally, RIVA and U-2932 were orthotopically transplanted into MISTRG mice and mice were treated for two weeks with Ibru or vehicle. Tumor cells were isolated from the bone marrow at the study endpoint. The total RNA was isolated and the mRNA profiles were generated by next-generation sequencing using the Illumina TruSeq mRNA stranded protocol. Results: We have combined 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. High Bcl-2 expression due to either BCL2 amplifications or translocations, in conjunction with chronic active BCR signalling accurately predict responses to dual Bcl-2/BTK inhibition.The combined 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 novel promising therapeutic strategy in DLBCL. Overall design: Examination of differential drug susceptibilities in DLBCL