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Colorectal cancer (CRC) often has a stubborn resistance to therapies, particularly when driven by MAPK pathway mutations such as KRAS and BRAF. This paper, published in Nature Magazine, from the team behind the ACRCelerate Accelerator Award and CRC-STARS, uncovers a critical mechanism behind therapeutic resistance: epithelial cell plasticity.

This CRUK-funded study,  led by the CRUK Scotland Centre and co-authored by researchers in the CRUK Oxford Centrefound that when therapies that block the MAPK pathway are used, the cells with these mutations quickly adapt by switching to a Wnt-associated stem phenotype, helping them survive treatment.

The good news? The team found that when plasticity is limited, such as in early metastatic disease or in tumours with RNF43 mutations, MAPK-targeted therapies produce strong responses.

Their work highlights that strategies to restrict cell-state transitions or exploit windows of vulnerability in early metastasis could improve outcomes with MAPK-targeted treatments.

Read the full paper in nature

Read more about the CRC-STARS Initiative, which is co-led by Professor Simon Leedham from the Nuffield Department of Medicine at the University of Oxford.

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