MAPK-driven epithelial cell plasticity drives colorectal cancer therapeutic resistance

作者：Mark White, Megan L. Mills, Laura M. Millett, Kathryn Gilroy, Yourae Hong, Lucas Zeiger, Robert U. Simpson, Shania M. Corry, A. Ligęza, Tamsin R.M. Lannagan, Susanti Susanti, Rachel A. Ridgway, Ayse Seda Yazgili, Lucile Grzesiak, Raheleh Amirkhah, Catriona A. Ford, Nikola Vlahov, Hannah Tovell, Leah Officer-Jones, Catherine Ficken, Rachel Pennie, Arafath K. Najumudeen, Alexander Raven, Nadia Nasreddin, Eklavya Chauhan, Andrew S. Papanastasiou, Colin Nixon, Vivienne Morrison, René Jackstadt, Janet Graham, Crispin Miller, Sarah J. Ross, Simon T. Barry, Valeria Pavet, Richard H. Wilson, John Le Quesne, Philip D. Dunne, Sabine Tejpar, Simon J. Leedham, Andrew D. Campbell, Owen J. Sansom · 发表于：Nature · 年份：2025 · DOI：10.1038/s41586-025-09916-w · 被引用次数：26 · 研究领域：Cancer Cells and Metastasis、Colorectal Cancer Treatments and Studies、Wnt/β-catenin signaling in development and cancer

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. Although 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. Here, given the development of KRAS inhibitors and licensing of BRAF inhibitor combinations 2–4 , 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, 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-targ...