Omer, Omer S;
Hertweck, Arnulf;
Roberts, Luke B;
Lo, Jonathan W;
Clough, Jennie N;
Jackson, Ian;
Pantazi, Eirini D;
... Lord, Graham M; + view all
(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.
| Type: | Article |
|---|---|
| Title: | Cyclin-dependent kinase 9 as a potential target for anti-TNF resistant inflammatory bowel disease |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.jcmgh.2022.05.011 |
| Publisher version: | https://doi.org/10.1016/j.jcmgh.2022.05.011 |
| Language: | English |
| Additional information: | © 2022 The Authors. Published by Elsevier Inc. on behalf of the AGA Institute under a Creative Commons license (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
| Keywords: | CDK9, Crohn’s disease, IBD, inflammation, ulcerative colitis |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10150425 |
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