MAPK-driven epithelial cell plasticity drives colorectal cancer therapeutic resistance.

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 transcript

SUBMITTER: White M 

PROVIDER: S-EPMC12916511 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature