Effect of small molecule IKKε/TBK1 inhibitors on cell lines from activated B-cell of diffuse large B-cell lymphoma

Outcomes in activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) remain poor and new targets for treatment are needed. NF-κB signalling pathways from the B-cell receptor and Toll-like receptors bear mutations and are constitutively active in ABC-DLBCL but inhibitors of the major components of these signalling pathways have not yet entered clinical practice. The IKK related kinases, IKKε/TBK1, have essential roles in innate immunity and regulate aspects of NF-κB signalling and other pathways. TBK1 mRNA expression is associated with clinical outcome and TBK1 and IKKε are variably expressed in human DLBCL. We explored the effects of small molecule IKKε/TBK1 inhibitors on DLBCL cell lines. Gene expression differences due to drug treatment were determined in both DMX3433 sensitive and resistant cell lines. GSEA showed four biologically relevant gene sets: “TNFα signalling via NF-κB” (MSigDB M5890) “Inflammatory Response” (MSigDB M10617), “Oxidative phosphorylation” (MSigDB M5936) and “IFNA response” (MSigDB M5911). There was enrichment for NF-κB pathway genes and for inflammatory response and oxidative phosphorylation genes in untreated cells but lower levels of leading edge genes in untreated cells in “IFNA response” such that type I IFN genes ISG15, IFIT2, IFIT3, MX1 and USP18 44 were induced on DMX3433 administration.