CDK9 Inhibition Could Be Target for Anti-TNF-Resistant Inflammatory Bowel Disease

Closeup shot of a woman suffering with stomach cramps at home
Researchers examined the effects of inhibiting transcription factor T-bet with CDK9 to treat patients with anti-TNF-resistant inflammatory bowel disease.

Cyclin-dependent kinase 9 (CDK9) inhibition may be a potential target for anti-tumor necrosis factor (TNF) therapy resistance among patients with inflammatory bowel disease (IBD), according to study results published in Cellular and Molecular Gastroenterology and Hepatology.

Using CD4+T cells from a wild-type naïve murine model, researchers evaluated the effect of CDK9 inhibition in the production of TNF-α and interferon (IFN)-γ. The T cells had been activated with anti-CD3 and anti-CD28 to induce Th1 cell differentiation. To evaluate the relevance for humans, activity of CDK9 inhibition was assessed in peripheral blood CD4+T cells from patients with IBD. Inhibited cells were transferred to mice with transmural colonic inflammation, resembling Crohn disease (CD). Tissues from colonic biopsies of patients with IBD were used to evaluate transcriptional regulation of TNF-α and IFN-γ.

Tissues were sourced from patients with CD (n=71) and ulcerative colitis (UC; n=56). The CD and UC cohorts had male and female ratios of 38:33 and 37:19; study participants had a mean age of 36.9 and 44.7 years; 41 and 32 patients had moderate to severe disease; and 12 and 5 were treatment naïve, respectively.

Concentrations of TNF-α (P =.0022) and IFN-γ (P =.026) were significantly reduced in cell cultures after CDK9 inhibition.

In cell cultures from patients with IBD, CD4+T cells had a dose-dependent relationship for TNF-α and IFN-γ concentrations 3 hours after CDK9 inhibition.

In the CD murine model, 6 days after treatment with flavopiridol (P =.0910) or NVP-2 (P =.6979) did not associate with changes to body weight or colon weight compared with dimethyl sulfoxide (DMSO) control. There was an improvement in colitis scores, however, among mice that received CDK9 inhibition and flavopiridol (P <.0001). Flow cytometry analysis revealed that systemic CDK9 inhibition targeted cytokine production at the site of inflammation (P =.0217).

In biopsy tissues, no differences in cell cycle status or cell viability were observed at 3 and 6 hours after CDK9 inhibition (all P ³.35). CDK9 inhibition was associated with significant reductions in TNF-α, IFN-g, interleukin (IL)-17A, and IL-22 cytokines (all P £.05). These observations remained similar when stratifying samples by whether they were sourced from patients who were anti-TNF responsive, resistant, or naïve.

Examining the expression profiles of cells prior to and after CDK9 inhibition, the top 250 genes repressed by NVP-2 were compared with pre- and post-treatment changes with anti-TNF therapy. The CDK9-repressed transcripts were associated with transcripts enriched among patients who were unresponsive to anti-TNF therapy (P <.0001). This trend was replicated using an independent cohort. Furthermore, the transcriptional signature of CDK9-repressed genes predicted response to anti-TNF therapy in CD (area under the curve [AUC], 0.90; P =.004) and, to a lesser extent, in UC (AUC, 0.80; P =.02).

“[Our study] demonstrate[s] the therapeutic potential of inhibiting P-TEFb/CDK9, a transcriptional elongation factor downstream of T-bet,” the study authors wrote. “Mechanistically, CDK9 inhibition primarily represses genes induced by the recruitment of P-TEFb following T cell activation. CDK9i-repressed genes are implicated in multiple immune pathways and are associated with anti-TNF nonresponsive IBD. This raises the prospect of CDK9 inhibition as a potential therapeutic option in anti-TNF-resistant disease.”

Reference

Omer OS, Hertweck A, Roberts LB, et al. Cyclin-dependent kinase 9 as a potential target for anti-TNF resistant inflammatory bowel disease. Cell Mol Gastroenterol Hepatol. Published online June 1, 2022. doi:10.1016/j.jcmgh.2022.05.011