Cyclin-dependent kinase 9 is a therapeutic target for anti-TNF resistant inflammatory bowel disease

The treatment of auto-inflammatory diseases is often limited by resistance to single cytokine blockade, primarily anti-TNF antibodies. This is a particularly important cause of treatment failure in inflammatory bowel disease (IBD). The transcription factor T-bet is a critical regulator of intestinal homeostasis and is genetically linked to mucosal inflammation by causal variation in its binding sites. However, transcription factors such as T-bet are difficult to target therapeutically. Using CDK9 inhibitors, we show that modulation of P-TEFb (cyclinT1/CDK9), a transcriptional elongation factor downstream of T-bet, potently represses genes responsible for pro-inflammatory signalling, and in particular genes regulated by T-bet. Remarkably, CDK9 inhibition targets genes that are highly expressed in anti-TNF resistant IBD and that predict non-response to anti-TNF therapy. Collectively, our findings reveal CDK9 as a potential target in anti-TNF resistant IBD, which has the potential for rapid translation to the clinic. poly-A+ RNA-Seq in human primary and secondary stimulated colonic CD4+ T cells from Crohn's disease and ulcerative colitis patients treated with NVP-2 or control

自身炎症性疾病的治疗常受限于单一细胞因子阻断疗法的耐药性，其中以抗TNF（Tumor Necrosis Factor）抗体治疗耐药最为突出。该耐药性是炎症性肠病（Inflammatory Bowel Disease，IBD）治疗失败的重要诱因。转录因子T-bet是肠道稳态的关键调控因子，其结合位点的因果性遗传变异使其与黏膜炎症存在遗传关联。然而，以T-bet为代表的转录因子难以实现治疗性靶向。本研究通过使用CDK9抑制剂证实，调控T-bet下游的转录延伸因子P-TEFb（cyclinT1/CDK9），可强效抑制介导促炎信号通路的基因表达，尤其是受T-bet调控的基因。值得注意的是，CDK9抑制的靶点基因在抗TNF耐药性IBD中呈高表达状态，且可有效预测对抗TNF治疗的无应答反应。综上，本研究发现CDK9可作为抗TNF耐药性IBD的潜在治疗靶点，具备快速向临床转化的潜力。本数据集涵盖从克罗恩病与溃疡性结肠炎患者体内获取的结肠原代及经二次刺激的CD4+ T细胞，经NVP-2或对照试剂处理后，对这些细胞开展poly-A+ RNA测序（poly-A+ RNA-Seq）。