克拉斯
西妥昔单抗
突变体
癌症研究
癌细胞
突变
生物
癌症
遗传学
基因
结直肠癌
作者
Jie Yang,Qiao-Li Wang,Guannan Wang,Jia-Cong Ye,Ziqian Li,Jing-Yun Wang,Zhaohui Liang,Shuxin Li,Cong Sun,Wenting Liao,Yijun Gao,Jing Wang,Yong Mao,Chunjing Yu,Guo‐Kai Feng,Mu‐Sheng Zeng
标识
DOI:10.1038/s41421-024-00699-4
摘要
Abstract 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.
科研通智能强力驱动
Strongly Powered by AbleSci AI