Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer
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.
Authors
- Wenjun Guo
- Yan Yan (ORCID: https://orcid.org/0000-0001-9859-3593)
- Zhaoyuan Fang (ORCID: https://orcid.org/0000-0002-0393-2052)
- Jianping Liao
- Hezhe Lu (ORCID: https://orcid.org/0009-0003-2408-2821)
- Yuanzhong Wu (ORCID: https://orcid.org/0000-0002-3577-7069)
- Rona Yaeger (ORCID: https://orcid.org/0000-0002-7233-5454)
- Rong Deng (ORCID: https://orcid.org/0000-0002-3431-5030)
- Wen‐Zhen Fang (ORCID: https://orcid.org/0000-0002-5880-3266)
- Xingyan Pan
- Qi Zhao (ORCID: https://orcid.org/0000-0002-8683-6145)
- J. Lao (ORCID: https://orcid.org/0009-0003-3063-5891)
- Wenfei Kang
- Yuetong Zhang (ORCID: https://orcid.org/0009-0003-6302-777X)
- Dan‐Yun Ruan
- Yijun Gao (ORCID: https://orcid.org/0000-0003-4978-3205)
- Feng Wang (ORCID: https://orcid.org/0000-0001-7668-9674)
- Yaxin Zhang (ORCID: https://orcid.org/0009-0005-0578-0346)
- Ruiping Wang (ORCID: https://orcid.org/0000-0003-4183-5795)
- Liqin Wang (ORCID: https://orcid.org/0000-0002-9881-6432)
- Zifeng Wang (ORCID: https://orcid.org/0000-0001-7400-5224)
- He Huang (ORCID: https://orcid.org/0000-0002-2723-1621)
- Lin Tian (ORCID: https://orcid.org/0000-0003-3661-4453)
- Weiping Zhou (ORCID: https://orcid.org/0000-0003-4013-3863)
- Jian Zheng
- Wenting Liao (ORCID: https://orcid.org/0000-0003-4953-3134)
- Yong She
- Jiaying Chen (ORCID: https://orcid.org/0009-0006-8903-171X)
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- Sun Yat-sen University (CN)
- Huazhong Agricultural University (CN)
- Sun Yat-sen University Cancer Center (CN)
- Second Affiliated Hospital of Zhejiang University (CN)
- Zhejiang University-University of Edinburgh Institute (CN)
- Institute of Zoology (CN)
Publication Details
- Journal
- Cancer Cell
- Published
- 2025-11-13
- DOI
- https://doi.org/10.1016/j.ccell.2025.10.010
- Citations
- 4
- Primary Topic
- Colorectal Cancer Treatments and Studies
- Type
- article
- Field-Weighted Citation Impact
- 4.18