La furina mantiene las señales promotoras de tumores en el cáncer colorrectal con mutaciones en los genes KRAS y BRAF al interactuar con el eje TGF-β1-COX-2 en una red de regulación recíproca.

KRAS and BRAF mutations drive colorectal cancer (CRC) progression by sustaining aberrant signaling and promoting therapeutic resistance. Here, we identify TGF-β1-COX-2 axis as a critical regulatory pathway mediated by Furin in CRC harboring KRAS or BRAF mutation. Genetic silencing or pharmacological inhibition of Furin in KRAS-mutant (KPN) and BRAF-mutant (BPN) tumor-derived cells suppressed tumor growth, reduced angiogenesis, and enhanced CD8⁺ T cell infiltration in mouse tumor models. KRAS- and BRAF-mutant organoids with impaired Furin activity exhibited increased sensitivity to 5-FU and irinotecan, whereas only KPN organoids were sensitive to oxaliplatin.

Mechanistically, Furin inhibition via shRNA or the Furin inhibitor MI1148 blocked IGF-1 receptor and TGF-β1 precursor maturation and signaling, which was associated with repressed COX-2 expression. Conversely, COX-2 overexpression elevated TGF-β1 levels, which in turn enhanced Furin expression, establishing a feed-forward loop that promoted tumor progression and angiogenesis.

Moreover, Furin inhibition largely disrupted the activity of multiple kinases linked to KRAS and BRAF oncogenic signaling. In CRC patient samples, Furin expression positively correlated with KRAS, BRAF, TGF-β1, and COX-2. Collectively, these findings identify Furin as a pivotal regulator of oncogenic signaling in KRAS- and BRAF-mutant CRC, and highlight the therapeutic potential of targeting the Furin-TGF-β1-COX-2 axis. Colorectal cancer often becomes harder to treat when tumor cells carry changes in genes called KRAS or BRAF.

This study investigated whether a protein-processing enzyme called Furin helps these cancer cells grow, resist treatment, and interact with their surrounding environment. Using colorectal cancer cells, organoids, mouse tumor models, and patient samples, we found that reducing Furin activity slowed tumor growth, improved the response to common chemotherapy drugs, reduced blood vessel formation, and increased the presence of cancer-killing immune cells. Mechanistically, Furin supported a tumor-promoting communication loop involving TGF-β1 and COX-2, two molecules linked to inflammation, cancer progression, and treatment resistance.

These findings suggest that blocking Furin, especially together with chemotherapy or anti-inflammatory strategies, may offer a new way to treat aggressive colorectal cancers with KRAS or BRAF mutations. Further studies are needed to develop safe and selective Furin-targeted therapies.