2. Academic Validation
  3. MAPK-driven epithelial cell plasticity drives colorectal cancer therapeutic resistance

MAPK-driven epithelial cell plasticity drives colorectal cancer therapeutic resistance

  • Nature. 2025 Nov 24. doi: 10.1038/s41586-025-09916-w.
Mark White # 1 2 3,  Megan L Mills # 1 2,  Laura M Millett # 1 2,  Kathryn Gilroy 1,  Yourae Hong 1 4,  Lucas B Zeiger 1,  Rosalin J Simpson 1,  Shania M Corry 5,  Amelia Ligeza 5,  Tamsin R M Lannagan 1,  Susanti Susanti 1,  Rachel A Ridgway 1,  Ayse S Yazgili 1,  Lucile Grzesiak 5,  Raheleh Amirkhah 6,  Catriona A Ford 1,  Nikola Vlahov 1,  Hannah Tovell 1,  Leah Officer-Jones 1,  Catherine Ficken 1,  Rachel Pennie 1,  Arafath K Najumudeen 1,  Alexander Raven 1,  Nadia Nasreddin 1,  Ekansh Chauhan 1 2,  Andrew S Papanastasiou 1,  Colin Nixon 1,  Vivienne Morrison 1,  Rene Jackstadt 7 8,  Janet S Graham 2 3,  Crispin J Miller 1,  Sarah J Ross 9,  Simon T Barry 9,  Valeria Pavet 1,  Richard H Wilson 2 3,  John Le Quesne 1 2,  Philip D Dunne 1 6,  Sabine Tejpar 4,  Simon Leedham 5 10,  Andrew D Campbell 11,  Owen J Sansom 12 13
Affiliations

Affiliations

  • 1 Cancer Research UK Scotland Institute, Glasgow, UK.
  • 2 School of Cancer Sciences, University of Glasgow, Glasgow, UK.
  • 3 Beatson West of Scotland Cancer Centre, Glasgow, UK.
  • 4 Digestive Oncology, Katholieke Universiteit Leuven, Leuven, Belgium.
  • 5 Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
  • 6 The Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK.
  • 7 Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany.
  • 8 Germany Cancer Progression and Metastasis Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 9 OTD Bioscience, Early Oncology, AstraZeneca, Cambridge, UK.
  • 10 Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, and Oxford NIHR Biomedical Research Centre, Oxford, UK.
  • 11 Cancer Research UK Scotland Institute, Glasgow, UK. [email protected].
  • 12 Cancer Research UK Scotland Institute, Glasgow, UK. [email protected].
  • 13 School of Cancer Sciences, University of Glasgow, Glasgow, UK. [email protected].
  • # Contributed equally.
PMID: 41286180 DOI: 10.1038/s41586-025-09916-w
Abstract

The colorectal epithelium is rapidly renewing, with remarkable capacity to regenerate following injury. In colorectal Cancer (CRC), this regenerative capacity can be co-opted to drive epithelial plasticity. While oncogenic MAPK signalling in CRC is common, with frequent mutations of both KRAS (40-50%) and BRAF (10%)1, inhibition of this pathway typically drives resistance clinically. Given the development of KRAS inhibitors, and licensing of BRAF inhibitor combinations2-4, we have interrogated key mechanisms of resistance to these agents in advanced preclinical CRC models. We show that oncogenic MAPK signalling induces epithelial state changes in vivo, driving adoption of a regenerative/revival stem like population, while inhibition leads to rapid transcriptional remodeling of both Kras- and Braf-mutant tumours, favoring a Wnt-associated, canonical stem phenotype. This drives acute therapeutic resistance in Kras- and delayed resistance in Braf-driven models. Importantly, where plasticity is restrained, such as in early metastatic disease, or through targeting ligand-dependent Wnt-pathway Rnf43 mutations, marked therapeutic responses are observed. This explains the super response to BRAF+EGFR targeted therapies previously observed in a BRAF/RNF43 co-mutant patient population, highlighting the criticality of cellular plasticity in therapeutic response. Together, our data provides clear insight into the mechanisms underpinning resistance to MAPK targeted therapies in CRC. Moreover, strategies that aim to corral stem cell fate, restrict epithelial plasticity or intervene when tumours lack heterogeneity may improve therapeutic efficacy of these agents.

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