The paper investigates the molecular basis for acquired therapeutic resistance in KRAS-mutant colorectal cancer (CRC) following dual inhibition of KRAS and EGFR. The research establishes that CRC cells utilize lineage plasticity, adopting a secretory Paneth-like cell state to survive the targeted therapy. Mechanistically, this adaptive transition is orchestrated by the SMAD1-FGFR3 signaling axis, which drives resistance by allowing the crucial MAPK pathway to reactivate within the surviving Paneth-like cell population. Through extensive preclinical models and analysis of human patient biopsies, the authors confirm that these resistant cells are significantly enriched after combination treatment. Ultimately, the study demonstrates that co-targeting FGFR3 with the existing dual KRAS-EGFR regimen successfully blocks this Paneth-like transition, offering a viable strategy to enhance anti-tumor efficacy. This discovery highlights the potential of inhibiting the SMAD1-FGFR3 axis to improve outcomes for patients facing resistance to KRAS-targeted therapies.

References:

• Zhang Y, Chen J, She Y, et al. Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer[J]. Cancer Cell, 2025.