Leicester Cancer Research Centre and Ernest and Helen Scott Haematological Research Unit, University of Leicester, Leicester, UK.
Domainex Ltd.,, Chesterford Research Park, Saffron Walden, UK.
J Cell Mol Med. 2020 Oct;24(19):11573-11582. doi: 10.1111/jcmm.15774. Epub 2020 Aug 28.
The IKK-related kinases, IKKε and TBK1, have essential roles in innate immunity in part through modifying MYD88 signalling from the Toll-like receptors to regulate NF-κB signalling. We investigated the expression and function of IKKε and TBK1, in diffuse large B-cell lymphoma (DLBCL). DLBCL cell lines and patient-derived xenografts were used to determine their sensitivity to IKKε and TBK1 inhibitors. To understand the function of IKKε and TBK1 secreted factors were determined following administration of inhibitors. Gene expression microarrays were used to determine the transcriptional effects of inhibitors. Higher TBK1 mRNA levels associated with poorer clinical outcome but IKKε and TBK1 were expressed in both germinal centre and non-germinal centre types of DLBCL. Survival of cell lines Ly10, Ly03 and Pfeiffer, and of some primary human lymphoma cells, was suppressed by a small molecule IKKε/TBK1 inhibitor, DMX3433. DMX3433 reduced IL-10 production from Ly10 and repressed NF-κB mediated transcription. Inhibition of IKKε and TBK1 warrants further investigation as a potential therapeutic route to suppress NF-κB signalling in lymphoma.
IKK 相关激酶 IKKε 和 TBK1 通过修饰 Toll 样受体的 MYD88 信号，调节 NF-κB 信号，在先天免疫中发挥重要作用。我们研究了 IKKε 和 TBK1 在弥漫性大 B 细胞淋巴瘤 (DLBCL) 中的表达和功能。使用 DLBCL 细胞系和患者来源的异种移植物来确定它们对 IKKε 和 TBK1 抑制剂的敏感性。为了了解 IKKε 和 TBK1 分泌因子的功能，在给予抑制剂后测定了它们的功能。使用基因表达微阵列确定了抑制剂的转录效应。较高的 TBK1 mRNA 水平与较差的临床结局相关，但 IKKε 和 TBK1 在生发中心和非生发中心类型的 DLBCL 中均有表达。小分子 IKKε/TBK1 抑制剂 DMX3433 抑制细胞系 Ly10、Ly03 和 Pfeiffer 以及一些原发性人类淋巴瘤细胞的存活。DMX3433 减少 Ly10 的 IL-10 产生，并抑制 NF-κB 介导的转录。IKKε 和 TBK1 的抑制作用值得进一步研究，作为抑制淋巴瘤中 NF-κB 信号的潜在治疗途径。
