哈尔滨工业大学胡颖课题组取得一项新突破。他们探明了法尼酰化驱动的KRAS相分离促进结肠肿瘤生长。该项研究成果发表在2026年5月27日出版的《细胞》上。
该研究组发现了一种调节机制，KRAS通过液-液相分离（LLPS）在细胞质中形成凝聚物，这是由其高变区（HVR）内C185残基的法尼酰化驱动的。这些冷凝物与结肠癌的晚期和不良预后有关。在功能上，KRAS凝聚物与Ras-转换酶1有效相互作用，促进RCE1凝固，增强KRAS加工，并促进其转运至质膜，从而放大KRAS信号，促进肿瘤生长。生长因子刺激进一步提高KRAS凝聚物的形成，强调其在肿瘤生物学中的作用。在治疗方面，筛选美国食品和药物管理局（FDA）批准的药物显示，他汀类药物，特别是匹伐他汀，通过抑制法尼酰化破坏KRAS LLPS，有效抑制结肠癌生长并提高G12Ci治疗的疗效。这些发现揭示了LLPS作为调节KRAS活性的机制，并为治疗干预提供了一个有希望的靶点。
研究人员表示，Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）是人类癌症中最常激活的驱动基因之一。
附：英文原文
Title: Farnesylation-driven KRAS phase separation promotes colon tumor growth
Author: 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
Issue&Volume: 2026-05-27
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.
DOI: 10.1016/j.cell.2026.05.002
Source: https://www.cell.com/cell/abstract/S0092-8674(26)00519-2