2. Academic Validation
  3. Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer

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

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: zhaoqi@sysucc.org.cn.
  • 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: liaowt@sysucc.org.cn.
  • 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: wangfeng@sysucc.org.cn.
  • 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: gaoyj@sysucc.org.cn.
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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