Reprogramming paneth-like plasticity: FGFR3 as a key to overcoming KRAS-EGFR resistance in CRC

Dual KRAS-epidermal growth factor receptor (EGFR) inhibition holds promise for KRAS-mutant colorectal cancer (CRC), yet drug resistance remains a key hurdle. This study by Zhang et al. identifies the SMAD family member 1 (SMAD1)-fibroblast growth factor receptor 3 (FGFR3) axis as the driver of Paneth-like lineage plasticity that mediates such resistance and demonstrates that FGFR3 targeting restores drug sensitivity and synergizes with dual pathway inhibition in preclinical models¹.