Fu Liangmin, Liao Wuyuan, Tan Youyan, Lin Hansen, Ye Kun, Zhou Xinwei, Lin Mingjie, Huang Kangbo, Chen Minyu, Wei Jietao, Feng Haoqian, Chen Yuhang, Chen Jinwei, Guan Bohong, Li Shan, Zhang Zhengkun, Yu Anze, Feng Zihao, Zhang Lizhen, Shu Guannan, Lu Jun, Chen Wei, Pan Yihui, Yang Jiefeng, Luo Junhang, Luo Li
Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 518880, China.
Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 528406, China.
Adv Sci (Weinh). 2025 Nov;12(44):e06367. doi: 10.1002/advs.202506367. Epub 2025 Sep 15.
Renal cell carcinoma (RCC) remains a formidable clinical challenge, characterized by a high propensity for metastasis and the frequent emergence of intrinsic or acquired resistance to targeted therapies. However, the molecular mechanisms underlying sunitinib resistance and tumor progression in RCC are not fully understood. This study aims to identify Twinfilin actin-binding protein (TWF2) as a key mediator of tumor aggressiveness and therapeutic resistance. TWF2 expression is markedly upregulated in RCC cells, particularly in sunitinib-resistant subtypes, and significantly associated with poor prognosis and therapeutic nonresponsiveness. Functional analyses demonstrate that TWF2 promotes RCC cell invasion, migration, metastasis, and sunitinib resistance by inhibiting the Hippo signaling. Mechanistically, TWF2 interacts with Yes-associated protein (YAP) via the binding residues: TWF2 M99 and YAP M225. By competitively displacing large tumor suppressor kinase 1, TWF2 prevents YAP ubiquitination and degradation, leading to its stabilization and subsequent nuclear translocation. Mutation of the M99 residue abolishes the tumor-promoting activity of TWF2. Furthermore, salvianolic acid E is identified as a small-molecule inhibitor of the TWF2-YAP interaction, and synergistically enhances sunitinib efficacy in RCC cell lines and patient-derived xenograft models. These findings highlight TWF2 as a promising therapeutic target for overcoming drug resistance in RCC.
肾细胞癌（RCC）仍然是一项严峻的临床挑战，其特点是转移倾向高，且经常出现对靶向治疗的内在或获得性耐药。然而，RCC中舒尼替尼耐药和肿瘤进展的分子机制尚未完全阐明。本研究旨在确定双丝状肌动蛋白结合蛋白（TWF2）是肿瘤侵袭性和治疗耐药性的关键介质。TWF2在RCC细胞中明显上调，尤其是在对舒尼替尼耐药的亚型中，并且与预后不良和治疗无反应显著相关。功能分析表明，TWF2通过抑制Hippo信号通路促进RCC细胞的侵袭、迁移、转移和舒尼替尼耐药。从机制上讲，TWF2通过结合残基：TWF2的M99和YAP的M225与Yes相关蛋白（YAP）相互作用。通过竞争性取代大肿瘤抑制激酶1，TWF2阻止YAP泛素化和降解，导致其稳定并随后发生核转位。M99残基的突变消除了TWF2的促肿瘤活性。此外，丹酚酸E被确定为TWF2-YAP相互作用的小分子抑制剂，并在RCC细胞系和患者来源的异种移植模型中协同增强舒尼替尼的疗效。这些发现突出了TWF2作为克服RCC耐药性的一个有前景的治疗靶点。
