Farnesylation-driven KRAS phase separation promotes colon tumor growth

Xingwen Wang; Yi Zhang; Minqiao Lu; Yafan Gong; Tianqi Guan; Guixue Hou; Yutong Wei; Meiqi Wang; Hao Liu; Lisha Huang; Shanliang Zheng; Qingyu Lin; Wenxin Zhang; Zhiyuan Xiang; Jiangwen Ma; Li Li; Hongxue Meng; Xinyuan Tong; Hongbin Ji; Jian Huang; Ying Hu

doi:10.1016/j.cell.2026.05.002

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. Epub 2026 May 27.

Authors

Xingwen Wang¹, Yi Zhang¹, Minqiao Lu¹, Yafan Gong¹, Tianqi Guan¹, Guixue Hou², Yutong Wei¹, Meiqi Wang¹, Hao Liu¹, Lisha Huang¹, Shanliang Zheng¹, Qingyu Lin¹, Wenxin Zhang¹, Zhiyuan Xiang¹, Jiangwen Ma¹, Li Li³, Hongxue Meng³, Xinyuan Tong⁴, Hongbin Ji⁵, Jian Huang⁶, Ying Hu⁷

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: huying@hit.edu.cn.

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.

MeSH terms

Animals
Cell Line, Tumor
Colonic Neoplasms* / drug therapy
Colonic Neoplasms* / metabolism
Colonic Neoplasms* / pathology
Endopeptidases
Humans
Mice
Phase Separation
Prenylation
Protein Prenylation
Proto-Oncogene Proteins p21(ras)* / chemistry
Proto-Oncogene Proteins p21(ras)* / genetics
Proto-Oncogene Proteins p21(ras)* / metabolism

Substances

Proto-Oncogene Proteins p21(ras)
KRAS protein, human
RCE1 protein, human
Endopeptidases