上海科技大学仓勇团队近日取得一项新成果。经过不懈努力，他们发现了HuR分子胶降解剂抑制BRAF突变型结直肠癌。相关论文发表在2026年6月10日出版的《自然》杂志上。

通过合理的化学文库设计和平行蛋白质组学筛选，该课题组人员发现dHuR是人抗原R （HuR）的分子胶降解剂，是一种驱动肿瘤生长、侵袭和治疗抵抗的RNA结合蛋白。dHuR与CRBN泛素连接酶结合，形成一个独特的苯并呋喃系结的复合表面，通过接合其β-发夹G-loop degron来吸收HuR作为新底物，这是三元配合物的低温电子显微镜结构所揭示的。dHuR通过诱导其外显子18跳变来消除BRAF的表达，并对BRAF突变的CRC肿瘤（包括对BRAF抑制剂产生耐药性的肿瘤）表现出卓越的抑制作用。最后，该团队进行了激酶组文库CRISPR筛选，发现EGFR或MEK的失活增强了dHuR的细胞毒性，从而建立了一种治疗难治性BRAF突变型CRC患者的组合策略。

据悉，BRAF功能获得性突变，特别是BRAF(V600E)，影响了大约10%的结直肠癌（CRC）患者，并且在有限的治疗干预下预示着预后不良。BRAF抑制剂如encorafenib由于BRAF二聚化驱动的MAPK通路再激活而无效。联合抑制BRAF和EGFR，虽然已被批准的治疗方法，导致短期的生存获益和频繁的治疗耐药和复发。

附：英文原文

Title: Molecular glue degraders of HuR suppress BRAF-mutant colorectal cancer

Author: Lu, Xiaocui, Wang, Xiuyun, Yang, Zheng, Wang, Xusheng, Wang, Lin, Xu, Chunhui, Lo, I-Chung, Geng, Chenlu, Wang, Lin, Pu, Yisheng, Zhang, Keyu, Zhu, Ziqiang, Ye, Lanxin, Huang, Jiayuan, Wei, Xiaofan, Bai, Fang, Zhu, Yanan, Qian, Xiaobing, Dou, Hao, Su, Hexiu, Cang, Yong

Issue&Volume: 2026-06-10

Abstract: BRAF gain-of-function mutations, particularly BRAF(V600E), affect roughly 10% of all patients with colorectal cancer (CRC), and portend poor prognosis with limited therapeutic interventions. BRAF inhibitors such as encorafenib are ineffective due to MAPK pathway reactivation driven by BRAF dimerization. Combined inhibition of BRAF and EGFR, although approved therapies, results in short survival benefits and frequent treatment resistance and relapse1,2,3. Here, through rational chemical library design coupled with parallel proteomic screening, we identified dHuR as a molecular glue degrader of human antigen R (HuR), an RNA-binding protein that drives tumour growth, invasion and therapy resistance. dHuR binds to the CRBN ubiquitin ligase to create a unique benzofuran-tethered composite surface to recruit HuR as a neosubstrate by engaging its β-hairpin G-loop degron, as revealed by the cryo-electron microscopy structure of the ternary complex. dHuR abrogated BRAF expression by inducing its exon 18 skipping, and demonstrated superior suppression of BRAF-mutant CRC tumours including those gaining resistance to BRAF inhibitors. Finally, we performed kinome library CRISPR screening and revealed that inactivation of EGFR or MEK enhanced dHuR cytotoxicity, thus establishing a combinatorial strategy to treat patients with refractory BRAF-mutant CRC.

DOI: 10.1038/s41586-026-10613-5

Source: https://www.nature.com/articles/s41586-026-10613-5