Omer, Omer S; Hertweck, Arnulf; Roberts, Luke B; Lo, Jonathan W; Clough, Jennie N; Jackson, Ian; Pantazi, Eirini D; ... Lord, Graham M; + view all Omer, Omer S; Hertweck, Arnulf; Roberts, Luke B; Lo, Jonathan W; Clough, Jennie N; Jackson, Ian; Pantazi, Eirini D; Irving, Peter M; MacDonald, Tom T; Pavlidis, Polychronis; Jenner, Richard G; Lord, Graham M; - view fewer (2022) Cyclin-dependent kinase 9 as a potential target for anti-TNF resistant inflammatory bowel disease. Cellular and Molecular Gastroenterology and Hepatology 10.1016/j.jcmgh.2022.05.011. (In press).

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Abstract

BACKGROUND AND AIMS: Resistance to single cytokine blockade, namely anti-TNF therapy, is a growing concern for patients with inflammatory bowel disease (IBD). The transcription factor T-bet is a critical regulator of intestinal homeostasis, is genetically linked to mucosal inflammation and controls the expression of multiples genes such as the pro-inflammatory cytokines IFN-γ and TNF. Inhibiting T-bet may therefore offer a more attractive prospect for treating IBD but remains challenging to target therapeutically. In this study, we evaluate the effect of targeting the transactivation function of T-bet using inhibitors of P-TEFb (CDK9-cyclin T), a transcriptional elongation factor downstream of T-bet. METHODS: Using an adaptive immune-mediated colitis model, human colonic lymphocytes from IBD patients and multiple large clinical datasets, we investigate the effect of CDK9 inhibitors on cytokine production and gene expression in colonic CD4+ T cells and link these genetic modules to clinical response in patients with IBD. RESULTS: Systemic CDK9 inhibition led to histological improvement of immune-mediated colitis and was associated with targeted suppression of colonic CD4+ T cell-derived IFN-γ and IL-17A. In colonic lymphocytes from IBD patients, CDK9 inhibition potently repressed genes responsible for pro-inflammatory signalling, and in particular genes regulated by T-bet. Remarkably, CDK9 inhibition targeted genes that were highly expressed in anti-TNF resistant IBD and that predicted non-response to anti-TNF therapy. CONCLUSION: Collectively, our findings reveal CDK9 as a potential target for anti-TNF resistant IBD, which has the potential for rapid translation to the clinic.

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