Professor Hu Ying's team from the Faculty of Life Sciences and Medicine, Harbin Institute of Technology (HIT), achieved a major breakthrough in elucidating the regulatory mechanisms and targeting strategies of the oncogene KRAS on May 27.
The research was published in the top-tier journal Cell under the title Farnesylation-Driven KRAS Phase Separation Promotes Colon Tumor Growth, marking the first time HIT has published as the primary completing institution in Cell.
The study reveals for the first time that farnesylation – a post-translational modification catalyzed by farnesyltransferase – drives KRAS to undergo liquid-liquid phase separation (LLPS), forming functional condensates in the cytoplasm that promote colon tumor growth. The team further discovered that statins can disrupt this process, providing novel strategies and potential drug candidates for the precision treatment of KRAS-driven tumors.
KRAS is one of the most important driver genes in human cancers. The recent FDA approval of the world's first KRAS inhibitor, AMG 510 (sotorasib), represented a historic milestone; however, patients often develop rapid resistance within months, necessitating the discovery of new (combination) targeting strategies. The field has primarily focused on KRAS activity regulation and signal transduction at the cell membrane, with limited understanding of the precise regulation and efficient trafficking mechanisms of KRAS in the cytoplasm.
Through studies of colon cancer clinical samples, the team discovered that KRAS protein forms numerous condensates in the cytoplasm, with higher quantities in tumor tissues compared to adjacent normal tissues. These condensates are closely associated with advanced tumor progression, invasion, metastasis, and poor patient prognosis. This phenomenon is also prevalent in lung cancer and pancreatic cancer, suggesting that KRAS condensates may represent a critical mechanism driving KRAS activation and tumor progression.
The team elucidated a novel phase separation-driving mechanism mediated by the strong hydrophobicity generated by C185 site-specific farnesylation, proposing the new concept that acylation modifications can drive protein phase separation. Additionally, KRAS condensates efficiently recruit RCE1 protein, promoting KRAS processing, maturation, and translocation to the plasma membrane. While growth factor stimulation is a well-established activator of KRAS signaling, this study discovered for the first time that growth factors promote KRAS condensate formation, thereby constructing a positive feedback loop that amplifies growth signals – an important supplement to the traditional understanding of growth factor-mediated KRAS activation.
The schematic diagram of farnesylation-driven KRAS phase separation promoting colon tumor growth. [Photo/hit.edu.cn]
By screening an FDA-approved drug library, the research team found that clinical lipid-lowering drugs, or statins, can disrupt KRAS phase separation, with pitavastatin demonstrating particularly significant efficacy. The team confirmed in animal models, patient-derived xenograft (PDX) models, and organoid models that pitavastatin can block KRAS phase separation, inhibit tumor growth, and significantly resensitize tumors resistant to the KRAS inhibitor AMG 510.
HIT is the primary completing institution of the paper. Professor Hu from the Faculty of Life Sciences and Medicine is the corresponding author, with Associate Researcher Wang Xingwen and doctoral student Zhang Yi serving as co-first authors.
The study received support from Doctor Hou Guixue of Shenzhen BGI Genomics Co, Professor Ji Hongbin of Westlake University, Associate Researcher Tong Xinyuan of Shanghai Chest Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Professor Li Li and Professor Meng Hongxue of Harbin Medical University Cancer Hospital, and Professor Huang Jian of Zhejiang University.
Paper link: https://www.cell.com/cell/abstract/S0092-8674(26)00519-2