Farnesylation-driven KRAS phase separation promotes colon tumor growth

  • Cell. 2026 Jul 9;189(14):4260-4275.e8. doi: 10.1016/j.cell.2026.05.002.
Xingwen Wang  1 ,  Yi Zhang  1 ,  Minqiao Lu  1 ,  Yafan Gong  1 ,  Tianqi Guan  1 ,  Guixue Hou  2 ,  Yutong Wei  1 ,  Meiqi Wang  1 ,  Hao Liu  1 ,  Lisha Huang  1 ,  Shanliang Zheng  1 ,  Qingyu Lin  1 ,  Wenxin Zhang  1 ,  Zhiyuan Xiang  1 ,  Jiangwen Ma  1 ,  Li Li  3 ,  Hongxue Meng  3 ,  Xinyuan Tong  4 ,  Hongbin Ji  5 ,  Jian Huang  6 ,  Ying Hu  7
Affiliations
  • 1. School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang 150001, China; Key Laboratory of Science and Engineering for the Multi-modal Prevention and Control of Major Chronic Diseases, Ministry of Industry and Information Technology, HIT Zhengzhou Research Institute, Zhengzhou 450000, China.
  • 2. BGI-SHENZHEN, Shenzhen 518083, China.
  • 3. The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150040, China.
  • 4. Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
  • 5. Westlake University School of Medicine, Hangzhou, Zhejiang 310030, China.
  • 6. 2nd Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, Zhejiang 130009, China.
  • 7. School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang 150001, China; Key Laboratory of Science and Engineering for the Multi-modal Prevention and Control of Major Chronic Diseases, Ministry of Industry and Information Technology, HIT Zhengzhou Research Institute, Zhengzhou 450000, China. Electronic address: [email protected].
PMID: 42202789 DOI: 10.1016/j.cell.2026.05.002
Abstract

Kirsten Rat Sarcoma viral oncogene homolog (KRAS) is one of the most frequently activated driver genes across human cancers. We identified a regulatory mechanism where KRAS forms condensates in the cytoplasm through liquid-liquid phase separation (LLPS), driven by farnesylation at the C185 residue within its hypervariable region (HVR). These condensates are associated with advanced stages and poor outcomes in colon Cancer. Functionally, KRAS condensates efficiently interact with Ras-converting enzyme 1 (RCE1), promoting RCE1 clustering, enhancing KRAS processing, and facilitating its translocation to the plasma membrane, which amplifies KRAS signaling and promotes tumor growth. Growth factor stimulation further elevates KRAS condensate formation, emphasizing its role in tumor biology. Therapeutically, screening US Food and Drug Administration (FDA)-approved drugs revealed that statins, particularly pitavastatin, disrupt KRAS LLPS by inhibiting farnesylation, effectively suppressing colon Cancer growth and enhancing the efficacy of G12Ci treatment. These findings uncover LLPS as a mechanism regulating KRAS activity and provide a promising target for therapeutic intervention.

Keywords
KRAS; RCE1; colon cancer; farnesylation; phase separation.
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