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Gene Signature-Based Approach Identified MEK1/2 as a Potential Target Associated With Relapse After Anti-TNFα
Kanae Gamo1, Yuumi Okuzono1, Masato Yabuki1
1Immunology Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
Background:
Anti-tumor necrosis factor alpha (anti-TNFα) therapy has become the mainstay of therapy for Crohn's disease (CD). However, post-therapy, the recurrence rate is still high. The aim of this study was to dissect the molecular mechanism for recurrence of CD treated with anti-TNFα therapy and investigate novel therapeutic options that could induce complete remission.
Methods:
We re-analyzed publicly available mucosal gene expression data from CD patients pre- and post-infliximab therapy to extract the transcriptional differences between responders and healthy controls. We used a systematic computational approach based on identified differences to discover novel therapies and validated this prediction through in vitro and in vivo experimentation.
Results:
We identified a set of 3545 anti-TNFα therapy-untreatable genes (TUGs) that are significantly regulated in intestinal epithelial cells, which remain altered during remission. Pathway enrichment analysis of these genes clearly showed excessive growth state and suppressed terminal differentiation, whereas immune components were clearly resolved. Through in silico screening strategy, we observed that MEK inhibitors were predicted to revert expression of genes dysregulated in infliximab responders. In vitro transcriptome analysis demonstrated that selective MEK1/2 inhibitor significantly normalized reference genes from TUGs. In addition, in vitro functional study proved that MEK1/2 inhibitor facilitated intestinal epithelial differentiation. Finally, using murine colitis model, administration of MEK1/2 inhibitor significantly improved diarrhea and histological score.
Conclusions:
Our data revealed the abnormalities in anti-TNFα responders' CD colons that would be cause of recurrence of CD. Also, we provided evidence regarding MEK1/2 inhibitor as a potential treatment against CD to achieve sustainable remission.
Insights
Recurrent Crohn's disease (CD) despite anti-tumor necrosis factor alpha (anti-TNFα) therapy may stem from persistent gene expression changes. MEK1/2 inhibitors show promise in restoring intestinal epithelial health and achieving sustained remission in CD.
Area of Science:
- Gastroenterology
- Molecular Biology
- Immunology
Background:
- Anti-tumor necrosis factor alpha (anti-TNFα) therapy is a primary treatment for Crohn's disease (CD), but high recurrence rates persist.
- Understanding the molecular mechanisms behind CD recurrence post-anti-TNFα therapy is crucial for developing improved treatments.
Purpose of the Study:
- To identify molecular mechanisms driving CD recurrence after anti-TNFα therapy.
- To explore novel therapeutic strategies, specifically MEK inhibitors, for achieving complete and sustained remission in CD.
Main Methods:
- Re-analysis of gene expression data from CD patients before and after infliximab therapy.
- Computational screening to identify potential therapeutic targets and in vitro/in vivo validation of MEK1/2 inhibitors.
Main Results:
- Identification of 3545 anti-TNFα therapy-untreatable genes (TUGs) in CD patients, indicating persistent excessive growth and impaired differentiation.
- In silico and in vitro studies confirmed that MEK1/2 inhibitors normalize TUG expression and promote intestinal epithelial differentiation.
- MEK1/2 inhibitor administration improved symptoms and histological scores in a murine colitis model.
Conclusions:
- Aberrant gene expression in intestinal epithelial cells contributes to CD recurrence even with anti-TNFα therapy.
- MEK1/2 inhibitors represent a promising therapeutic approach for Crohn's disease, potentially leading to sustainable remission.