| First Author | White M | Year | 2026 |
| Journal | Nature | Volume | 650 |
| Issue | 8102 | Pages | 748-758 |
| PubMed ID | 41286180 | Mgi Jnum | J:388081 |
| Mgi Id | MGI:8355584 | Doi | 10.1038/s41586-025-09916-w |
| Citation | White M, et al. (2026) MAPK-driven epithelial cell plasticity drives colorectal cancer therapeutic resistance. Nature 650(8102):748-758 |
| abstractText | 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-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. |
