Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer

  • Cancer Cell. 2025 Nov 13:S1535-6108(25)00451-9. doi: 10.1016/j.ccell.2025.10.010.
Yuetong Zhang  1 ,  Jiaying Chen  2 ,  Yong She  3 ,  Zhaoyuan Fang  4 ,  Yaxin Zhang  1 ,  Danyun Ruan  5 ,  Wenjun Guo  1 ,  Jianping Liao  1 ,  Weiping Zhou  6 ,  Jianpei Lao  3 ,  Weicheng Fang  1 ,  Xingyan Pan  1 ,  Wenfei Kang  7 ,  Zifeng Wang  1 ,  Yuanzhong Wu  1 ,  Rong Deng  1 ,  Lin Tian  1 ,  Liqin Wang  1 ,  Huilin Huang  1 ,  Jian Zheng  1 ,  Yan Yan  8 ,  Hezhe Lu  6 ,  Ruiping Wang  1 ,  Rona Yaeger  9 ,  Qi Zhao  10 ,  Wenting Liao  11 ,  Feng Wang  12 ,  Yijun Gao  13
Affiliations
  • 1. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
  • 2. Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P.R. China; Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, P.R. China.
  • 3. Bioinformatics Platform, Department of Experimental Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P.R. China.
  • 4. Department of Colorectal Surgery and Oncology of the Second Affiliated Hospital, and Centre of Biomedical Systems and Informatics of Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310058, China.
  • 5. Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, P.R. China; Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, China.
  • 6. State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
  • 7. Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 8. College of Biomedicine and Health and College of Life Science and Technology, Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan, Hubei 430070, China.
  • 9. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 10. Bioinformatics Platform, Department of Experimental Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P.R. China. Electronic address: [email protected].
  • 11. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China. Electronic address: [email protected].
  • 12. Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P.R. China; Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, P.R. China. Electronic address: [email protected].
  • 13. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China. Electronic address: [email protected].
PMID: 41237766 DOI: 10.1016/j.ccell.2025.10.010
Abstract

While dual KRAS and epidermal growth factor receptor (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 discover 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 reveals that CRC cells evade dual therapy by transitioning into a Paneth-like state. Through integrated transcriptomic analysis and CRISPR genetic screening, we identify SMAD1 as a key regulator of this lineage plasticity, promoting resistance by directly activating FGFR3. Genetic or pharmacological inhibition of FGFR3 prevents the Paneth-like transition, restores drug sensitivity, and synergizes with KRAS-EGFR inhibition across multiple preclinical models. These findings reveal that the SMAD1-FGFR3 axis triggers Paneth-like plasticity to drive KRAS-EGFR dual therapy resistance in CRC and highlight FGFR3 blockade as a promising strategy to overcome plasticity-driven drug tolerance.

Keywords
KRAS mutant colorectal cancer; Paneth-like cell state; drug resistance; dual KRAS and EGFR-targeted therapy; lineage plasticity; trans-differentiation.
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