DOP122 Unravelling the molecular landscape of anti-TNF failure in Ulcerative Colitis identifies MEK/ERK inhibitors as putative therapeutic candidates
Authors: Thomas J P , Cozzetto D , Saifuddin A , Gul L , Modos D , Korcsmaros T , Powell N 
Published: January 2025

Abstract

Background
Ulcerative colitis (UC) patients with prior anti-TNF treatment failure exhibit reduced response rates to subsequent advanced therapies1. As anti-TNF agents are frequently positioned as first-line biologics in UC, those with the greatest need for new therapeutic options often experience limited efficacy with alternative treatments. However, the mechanistic basis of anti-TNF failure remains poorly understood. This study aimed to investigate the clinical and molecular phenotype of UC patients who previously failed anti-TNF therapy.

Methods
Data from the UNIFI phase 3 trial in moderate-to-severe UC, including clinical features and pre-treatment mucosal microarray profiles of 275 anti-TNF failure and 262 anti-TNF naïve patients, were analysed2. Differential gene expression, pathway enrichment, cellular deconvolution, gene regulatory network (GRN), and upstream signalling analyses were performed. Connectivity Map analysis was utilised to identify potential therapeutic candidates.

Results
Patients with prior failure to anti-TNF therapy exhibited a more severe clinical phenotype characterised by increased disease duration, CRP, and histological inflammation. After correcting for these clinical features, 11 genes emerged as significantly differentially expressed (absolute log2 fold change &gt;0.5, adjusted p-value &lt;0.1) between the anti-TNF failed and anti-TNF naïve patient groups. Gene set enrichment analysis revealed upregulation of extracellular matrix (ECM)- and stroma-related biological pathways in anti-TNF failure (Figure 1A). PROGENy pathway perturbation analysis indicated increased activity of EGFR, MAPK, and PI3K pathways in this group. Cellular deconvolution analysis using xCell3 revealed increased stromal cell abundance and reduced T cell populations in the colonic mucosa following anti-TNF failure (Figure 1B). GRN analysis suggested that transcriptional dysregulation may underlie these cellular and functional changes, with ERK1 and CDK2 identified as key upregulated upstream signalling proteins. Connectivity Map analysis using the iLINCS database4 identified compounds targeting the MAPK pathway, particularly MEK/ERK inhibitors, as promising candidates to counteract the transcriptomic landscape associated with anti-TNF failure (Figure 2).

Conclusion
Failure to anti-TNF therapy in UC patients is characterised by remodelling of the colonic stroma and ECM, and is underpinned by upstream signalling and transcriptional dysregulation. MEK/ERK inhibitors may be putative drug candidates for overcoming anti-TNF failure and improving clinical outcomes in this difficult-to-treat patient group.

References
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2.Sands BE, Sandborn WJ, Panaccione R, et al. Ustekinumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2019;381(13):1201-1214. doi:10.1056/NEJMoa19007503.
3.Aran D, Hu Z, Butte AJ. xCell: digitally portraying the tissue cellular heterogeneity landscape. Genome Biol. 2017;18(1):220. doi:10.1186/s13059-017-1349-14.
4.Pilarczyk M, Fazel-Najafabadi M, Kouril M, et al. Connecting omics signatures and revealing biological mechanisms with iLINCS. Nat Commun. 2022;13(1):4678. doi:10.1038/s41467-022-32205-3