用于治疗 KRAS 突变癌症的泛 KRAS 降解剂。

IF 13 1区 生物学 Q1 CELL BIOLOGY Cell Discovery Pub Date : 2024-06-28 DOI:10.1038/s41421-024-00699-4
Jie Yang, Qiao-Li Wang, Guan-Nan Wang, Jia-Cong Ye, Zi-Qian Li, Jing-Yun Wang, Zhao-Hui Liang, Shu-Xin Li, Cong Sun, Wen-Ting Liao, Yi-Jun Gao, Jing Wang, Yong Mao, Chunjing Yu, Guo-Kai Feng, Mu-Sheng Zeng
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引用次数: 0

摘要

KRAS 突变在多种致命癌症中非常普遍,这些突变形式的 KRAS 在推动癌症进展和产生抗药性方面发挥着至关重要的作用。虽然针对特定 KRAS 突变体的小分子药物的开发取得了进展,但不可药用突变体的存在和二次突变的出现仍给 KRAS 突变癌症的临床治疗带来了挑战。在这项研究中,我们开发了一种名为肿瘤靶向 KRAS 降解剂(TKD)的新型分子工具,它能有效靶向多种 KRAS 突变体。TKD由一个KRAS结合纳米抗体、一个选择性靶向癌细胞的细胞穿透肽和一个溶酶体结合基团组成。我们的数据显示,TKD可选择性地与癌细胞中的KRAS结合,并通过溶酶体依赖过程有效地诱导KRAS降解。在功能上,TKD能抑制肿瘤生长,且无明显副作用,并能增强PD-1抗体和西妥昔单抗的抗肿瘤作用。这项研究不仅为开发针对 "不可药用 "蛋白的药物提供了一种策略,而且揭示了 TKD 是一种治疗 KRAS 突变癌症的有前途的疗法。
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A pan-KRAS degrader for the treatment of KRAS-mutant cancers.

KRAS mutations are highly prevalent in a wide range of lethal cancers, and these mutant forms of KRAS play a crucial role in driving cancer progression and conferring resistance to treatment. While there have been advancements in the development of small molecules to target specific KRAS mutants, the presence of undruggable mutants and the emergence of secondary mutations continue to pose challenges in the clinical treatment of KRAS-mutant cancers. In this study, we developed a novel molecular tool called tumor-targeting KRAS degrader (TKD) that effectively targets a wide range of KRAS mutants. TKD is composed of a KRAS-binding nanobody, a cell-penetrating peptide selectively targeting cancer cells, and a lysosome-binding motif. Our data revealed that TKD selectively binds to KRAS in cancer cells and effectively induces KRAS degradation via a lysosome-dependent process. Functionally, TKD suppresses tumor growth with no obvious side effects and enhances the antitumor effects of PD-1 antibody and cetuximab. This study not only provides a strategy for developing drugs targeting "undruggable" proteins but also reveals that TKD is a promising therapeutic for treating KRAS-mutant cancers.

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来源期刊
Cell Discovery
Cell Discovery Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
24.20
自引率
0.60%
发文量
120
审稿时长
20 weeks
期刊介绍: Cell Discovery is a cutting-edge, open access journal published by Springer Nature in collaboration with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). Our aim is to provide a dynamic and accessible platform for scientists to showcase their exceptional original research. Cell Discovery covers a wide range of topics within the fields of molecular and cell biology. We eagerly publish results of great significance and that are of broad interest to the scientific community. With an international authorship and a focus on basic life sciences, our journal is a valued member of Springer Nature's prestigious Molecular Cell Biology journals. In summary, Cell Discovery offers a fresh approach to scholarly publishing, enabling scientists from around the world to share their exceptional findings in molecular and cell biology.
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