MEK inhibition induces persistent growth arrest through Wnt hyperactivation in KRAS wild-type colorectal cancer

Although the canonical EGFR/KRAS/MAPK pathway plays a central role in CRC tumorigenesis, and KRAS/BRAF mutations define only a subset of tumors, the fate of KRAS wild-type CRC cells surviving MEK inhibition remains poorly understood. Using patient-derived organoids (PDOs) and tissue samples, we detected heterogeneous MAPK pathway activity and found that MEK inhibition induces sustained growth arrest that persists after drug withdrawal and even in the presence of EGF.

This low-proliferative state was accompanied by a transcriptional shift towards a stem cell–like program characterized by high Wnt pathway activity, without evidence of increased senescence and without elevated expression of genes associated with high-plasticity tumor cell state. Importantly, we proved that Wnt hyperactivation recapitulates the effects of MEK inhibition in surviving KRAS wild-type PDOs, suggesting a functional link between MEK inhibition and Wnt-driven reprogramming.