军事医学2026，Vol.50Issue(7)：505-514,10.DOI:10.7644/j.issn.1674-9960.2026-00046
利用组学技术筛选结直肠癌中KRAS G12D抑制剂耐药候选治疗靶点
Omics-based screening of candidate therapeutic targets for KRAS G12D inhibitor resistance in colorectal cancer
摘要
Abstract
Objective To identify potential therapeutic targets for overcoming resistance to KRAS G12D inhibitors in colorectal cancer using quantitative proteomic strategies.Methods MRTX1133-resistant KRAS G12D-mutant colorectal cancer cell lines were established via dose escalation and verified.Quantitative proteomic analysis was conducted using data-independent acquisition(DIA).Differentially expressed proteins were identified with the Limma package under the thresholds of adj.P<0.05 and|logFC|>1.Gene set enrichment analysis(GSEA)was conducted based on the Reactome database.Functional enrichment was analyzed using GO and KEGG databases.Protein-protein interaction(PPI)networks were constructed and analyzed using the STRING database.Results MRTX1133-resistant cell lines were constructed.A total of 7124 proteins were quantified,88 of which were significantly differentially expressed,including NF-κB inhibitor-interacting Ras-like 1(NKIRAS1),IQ motif-containing protein B1(IQCB1),keratin 17(KRT17),and serine protease 2(PRSS2).Enrichment analysis found that hypoxia,cytoskeleton organization,and amino acid metabolism pathways were significantly dysregulated.In addition,the hypoxia-related F-actin monooxygenase MICAL1 might contribute to resistance to KRAS G12D inhibitors by activating the WNT/β-catenin signaling pathway.Conclusion Resistance to the KRAS G12D inhibitor MRTX1133 is closely related to the dysregulation of hypoxia,cytoskeleton,and amino acid metabolism pathways.NKIRAS1,IQCB1,KRT17,PRSS2,and MICAL1 may serve as novel candidate targets for reversing drug resis-tance.In particular,MICAL1 may promote resistance to KRAS G12D inhibitors by activating the WNT/β-catenin pathway.关键词
定量蛋白质组学/结直肠癌/KRAS G12D抑制剂/耐药Key words
quantitative proteomics/colorectal cancer/KRAS G12D inhibitor/drug resistance分类
医药卫生引用本文复制引用
洪若琳,郝杨,冯峻德,崔春萍..利用组学技术筛选结直肠癌中KRAS G12D抑制剂耐药候选治疗靶点[J].军事医学,2026,50(7):505-514,10.基金项目
国家重点研发计划项目(2021YFA1300200,2022YFC3401500) （2021YFA1300200,2022YFC3401500）
