MAPK-driven epithelial cell plasticity drives colorectal cancer therapeutic resistance
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. Although oncogenic MAPK signalling in CRC is common, with frequent mutations of both KRAS (40-50%) and BRAF (10%)<sup>1</sup>, inhibition of this pathway typically drives resistance clinically. Here, given the development of KRAS inhibitors and licensing of BRAF inhibitor combinations<sup>2-4</sup>, 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, whereas inhibition leads to rapid transcriptional remodelling of both Kras-mutant and Braf-mutant tumours, favouring a WNT-associated, canonical stem phenotype. This drives acute therapeutic resistance in Kras-driven and delayed resistance in Braf-driven models. 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 provide 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.
Authors
- Alexander Raven (ORCID: https://orcid.org/0000-0003-4409-9543)
- Mark White (ORCID: https://orcid.org/0000-0002-6309-3254)
- Lucas Zeiger (ORCID: https://orcid.org/0000-0002-8712-3112)
- Sabine Tejpar (ORCID: https://orcid.org/0000-0003-3281-8643)
- Catriona A. Ford (ORCID: https://orcid.org/0000-0003-3991-6369)
- Yourae Hong (ORCID: https://orcid.org/0000-0001-6683-433X)
- Catherine Ficken (ORCID: https://orcid.org/0000-0003-4764-210X)
- Nikola Vlahov (ORCID: https://orcid.org/0009-0002-8649-6109)
- Susanti Susanti (ORCID: https://orcid.org/0000-0001-9704-5157)
- René Jackstadt (ORCID: https://orcid.org/0009-0005-6246-2133)
- Simon T. Barry (ORCID: https://orcid.org/0000-0002-8511-0588)
- Kathryn Gilroy (ORCID: https://orcid.org/0000-0003-4607-194X)
- Colin Nixon (ORCID: https://orcid.org/0000-0002-8085-2160)
- Richard H. Wilson (ORCID: https://orcid.org/0000-0001-8018-7730)
- Valeria Pavet (ORCID: https://orcid.org/0000-0002-4472-6503)
- Rachel A. Ridgway (ORCID: https://orcid.org/0000-0003-0198-8244)
- John Le Quesne (ORCID: https://orcid.org/0000-0003-3552-7446)
- Nadia Nasreddin (ORCID: https://orcid.org/0000-0002-3025-6213)
- Tamsin R.M. Lannagan (ORCID: https://orcid.org/0000-0002-8206-8898)
- Andrew D. Campbell (ORCID: https://orcid.org/0000-0003-3930-1276)
- Owen J. Sansom (ORCID: https://orcid.org/0000-0001-9540-3010)
- Arafath K. Najumudeen (ORCID: https://orcid.org/0000-0002-3764-5721)
- Andrew S. Papanastasiou (ORCID: https://orcid.org/0000-0002-8888-0633)
- Philip D. Dunne (ORCID: https://orcid.org/0000-0001-9160-283X)
- Janet Graham (ORCID: https://orcid.org/0000-0002-2048-2698)
- Crispin Miller (ORCID: https://orcid.org/0000-0003-4341-1283)
- Megan L. Mills (ORCID: https://orcid.org/0009-0000-0922-7912)
- Hannah Tovell (ORCID: https://orcid.org/0000-0002-2473-7256)
- Sarah J. Ross (ORCID: https://orcid.org/0000-0001-8759-1728)
- Rachel Pennie (ORCID: https://orcid.org/0009-0001-4796-7388)
- Simon J. Leedham (ORCID: https://orcid.org/0000-0003-1476-6982)
- Raheleh Amirkhah (ORCID: https://orcid.org/0000-0003-3494-271X)
- Shania M. Corry
- Leah Officer-Jones (ORCID: https://orcid.org/0000-0002-3690-2386)
- Lucile Grzesiak (ORCID: https://orcid.org/0000-0002-7351-2045)
- Ayse Seda Yazgili (ORCID: https://orcid.org/0000-0001-8485-9653)
- Laura M. Millett (ORCID: https://orcid.org/0009-0000-7596-4275)
- Vivienne Morrison (ORCID: https://orcid.org/0009-0009-1022-8969)
- Robert U. Simpson (ORCID: https://orcid.org/0009-0001-8571-7275)
- Eklavya Chauhan (ORCID: https://orcid.org/0000-0002-1096-0625)
- A. Ligęza (ORCID: https://orcid.org/0009-0006-9075-3138)
Institutions
- Queen's University Belfast (GB)
- Centre for Human Genetics (GB)
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- Beatson West of Scotland Cancer Centre (GB)
- Cancer Research UK (GB)
- John Radcliffe Hospital (GB)
- University of Oxford (GB)
- Oxford BioMedica (United Kingdom) (GB)
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (DE)
- AstraZeneca (Germany) (DE)
- University of Glasgow (GB)
- KU Leuven (BE)
Publication Details
- Journal
- Nature
- Published
- 2025-11-24
- DOI
- https://doi.org/10.1038/s41586-025-09916-w
- Citations
- 5
- Primary Topic
- Cancer Cells and Metastasis
- Type
- article
- Field-Weighted Citation Impact
- 5.23