Therapeutic implications include combining MAPK inhibitors with Wnt modulators or stem cell regulatory axis agents, aiming to curb phenotypic switching for durable responses.

The study calls for targeting not just oncogenic drivers but also cancer cells’ capacity for phenotypic fluidity and regeneration to overcome CRC resistance.

The evolutionary paths to resistance differ by genetic context: KRAS-driven tumors react immediately, whereas BRAF-driven tumors develop resistance more slowly.

MAPK-driven epithelial cell plasticity fuels regenerative, stem-like states in colorectal cancer (CRC) cells, contributing to therapeutic resistance.

Oncogenic MAPK signaling, with KRAS mutations in roughly 40–50% and BRAF mutations around 10%, drives epithelial state changes in vivo, while MAPK inhibition rapidly remodels transcriptional programs to push tumors toward a canonical Wnt-associated stem phenotype.

Overall, the findings suggest a paradigm shift toward therapies that manage epithelial plasticity in concert with MAPK blockade to achieve durable CRC responses.

Understanding the temporal dynamics of resistance and epithelial plasticity points to identifying optimal treatment windows, especially in tumor stages with lower intra-tumoral heterogeneity.

Clinical relevance is underscored by exceptional responses to combined BRAF and EGFR therapies in BRAF/RNF43 co-mutant tumors, highlighting plasticity’s role in outcomes.

Detailed clinical observations of exceptional responses in BRAF and RNF43 co-mutant tumors under BRAF plus EGFR inhibition can be explained by restricted plasticity, advocating integrated genetic and phenotypic profiling.

Epithelial plasticity sits at the center of resistance; restricting plasticity or targeting Wnt pathway components (including RNF43-related ligands) enhances MAPK inhibitor efficacy.

Restraining plasticity early in metastasis or targeting ligand-dependent Wnt pathway mutations (e.g., RNF43) yields strong therapeutic responses.

KRAS-mutant tumors show acute resistance to MAPK inhibitors due to rapid plasticity and Wnt-program activation, while BRAF-mutant tumors experience delayed resistance.