Protein‐Targeted Glycan Editing on Living Cells Disrupts KRAS Signaling
Yiran Li, Fan Huo, Liusheng Chen, Haiqi Wang, Jianzhuang Wu, Peiwen Zhang, Nan Feng, Wei Li, Lan Wang, Yichun Wang, Xiaojian Wang, Xiaoliang Yang, Zhiqiang Lu, Yang Mao, Chao Yan, Lin Ding, Huangxian Ju
Abstract
Abstract The frequent mutation of KRAS oncogene in some of the most lethal human cancers has spurred incredible efforts to develop KRAS inhibitors, yet only one covalent inhibitor for the KRAS G12C mutant has been approved to date. New venues to interfere with KRAS signaling are desperately needed. Here, we report a “localized oxidation‐coupling” strategy to achieve protein‐specific glycan editing on living cells for disrupting KRAS signaling. This glycan remodeling method exhibits excellent protein and sugar specificity and is applicable to different donor sugars and cell types. Attachment of mannotriose to the terminal galactose/ N ‐acetyl‐D‐galactosamine epitopes of integrin α v β 3 , a membrane receptor upstream of KRAS, blocks its binding to galectin‐3, suppresses the activation of KRAS and downstream effectors, and mitigates KRAS‐driven malignant phenotypes. Our work represents the first successful attempt to interfere with KRAS activity by manipulating membrane receptor glycosylation.