Paneth-like transition drives resistance to KRAS/EGFR Dual Therapy in Colorectal Cancer (PRJCA044370)
While dual KRAS and EGFR inhibition shows promise in treating KRAS-mutant colorectal cancer (CRC), resistance remains a major challenge. Using genetically engineered mouse models, patient derived organoids and xenografts, as well as clinical specimens, we discovered that colorectal tumors surviving combined KRAS and EGFR inhibition acquire a Paneth-like cell state - a secretory lineage typically confined to the intestinal crypt. Lineage tracing revealed that CRC cells evade KRAS/EGFR-targeted therapy by transitioning into Paneth-like state. Through integrated transcriptomic analysis and CRISPR/Cas9 genetic screening, we identified SMAD1 as a key regulator of this lineage plasticity, promoting resistance by directly activating FGFR3. Genetic or pharmacological inhibition of FGFR3 prevented the Paneth-like transition, restored drug sensitivity, and synergized with KRAS/EGFR inhibitors across multiple preclinical models. These findings reveal that SMAD1/FGFR3 axis triggers Paneth-like Plasticity to drive KRAS/EGFR therapy resistance in CRC and highlight FGFR3 blockade as a promising strategy to overcome plasticity-driven drug tolerance.