Rheumatism drug teriflunomide shows subtype-dependent effects in breast cancer cells

Teriflunomide, the active metabolite of the rheumatoid arthritis drug leflunomide, has drawn attention as a candidate for cancer drug repurposing because it does more than inhibit dihydroorotate dehydrogenase (DHODH), its canonical target. A new open-access study in BMC Pharmacology and Toxicology reports that the drug reduces tumour-cell fitness in both luminal and triple-negative breast cancer cell models, but that its downstream molecular effects differ sharply between the two subtypes.

Researchers treated luminal MCF-7 cells and triple-negative MDA-MB-231 cells with teriflunomide and analysed the response using cell viability, clonogenicity and migration assays, label-free proteomics, KEGG pathway analysis and phospho-kinase profiling. Treated cells were compared with untreated counterparts and with non-tumorigenic MCF-10A cells to distinguish treatment-associated proteomic remodelling from baseline differences between cancerous and normal-like cells.

In MCF-7 cells, the treatment was associated with a clearer shift in protein abundance and with suppression of growth-related phospho-signalling, particularly along the PI3K/AKT/mTOR/p70S6K/RSK axis, a central growth-promoting signalling cascade. In contrast, MDA-MB-231 cells showed a more limited abundance-level proteomic shift but broader activation of phospho-signalling involving EGFR/Src/STAT3, MAPK and AKT-related pathways, a pattern the authors interpret as adaptive rewiring under drug-induced stress.

One of the study’s technical insights is that changes in kinase abundance were often uncoupled from changes in kinase activation state, meaning that integrating proteomic and phospho-kinase data was necessary to see the full picture of how the cells responded.

To assess the relevance of these markers beyond the cell culture setting, the team used TCGA data for validation. Most of the top-regulated proteins differed between breast cancer tissue and normal tissue, while only a subset varied across pathological stages, which the authors say supports their potential as candidates for combination strategies rather than as stage-specific markers.

The authors conclude that teriflunomide exerts subtype-dependent anticancer effects in breast cancer cells and reshapes signalling networks in a context-specific manner, supporting further evaluation of the drug in subtype-informed combination strategies targeting adaptive kinase and metabolic pathways. Because the findings come from in vitro cell models, they represent early mechanistic evidence rather than demonstrated clinical benefit, and the authors note that the article is an accepted manuscript shared early, subject to further edits before the final version of record.

Subject of Research: Subtype-dependent proteomic and phospho-kinase effects of teriflunomide in breast cancer cell models

Article Title: Teriflunomide modulates proteomic and phospho-kinase landscapes in breast cancer: evidence for non-canonical effects beyond DHODH inhibition

Article References: Iskender, B., Sarihan, M., Kongur, Z. S., Kocyigit, E., & Kasap, M. (2026). Teriflunomide modulates proteomic and phospho-kinase landscapes in breast cancer: evidence for non-canonical effects beyond DHODH inhibition. BMC Pharmacology and Toxicology. https://doi.org/10.1186/s40360-026-01265-2

Image Credits: AI Generated

DOI: 10.1186/s40360-026-01265-2

Keywords: teriflunomide, drug repurposing, breast cancer, DHODH, phospho-kinase, proteomics, MCF-7, MDA-MB-231, PI3K/AKT/mTOR, EGFR/Src/STAT3, TCGA, cell culture