Proteomic characterization of gastric cancer response to chemotherapy and targeted therapy reveals potential therapeutic strategies

Author:

Li YanORCID,Xu ChenORCID,Wang BingORCID,Xu FujiangORCID,Ma FahanORCID,Qu Yuanyuan,Jiang DongxianORCID,Li KaiORCID,Feng JinwenORCID,Tian ShaORCID,Wu XiaohuiORCID,Wang YunzhiORCID,Liu YangORCID,Qin ZhaoyuORCID,Liu Yalan,Qin JingORCID,Song QiORCID,Zhang XiaoleiORCID,Sujie Akesu,Huang Jie,Liu TianshuORCID,Shen KuntangORCID,Zhao Jian-YuanORCID,Hou YingyongORCID,Ding ChenORCID

Abstract

AbstractChemotherapy and targeted therapy are the major treatments for gastric cancer (GC), but drug resistance limits its effectiveness. Here, we profile the proteome of 206 tumor tissues from patients with GC undergoing either chemotherapy or anti-HER2-based therapy. Proteome-based classification reveals four subtypes (G-I–G-IV) related to different clinical and molecular features. MSI-sig high GC patients benefit from docetaxel combination treatment, accompanied by anticancer immune response. Further study reveals patients with high T cell receptor signaling respond to anti-HER2-based therapy; while activation of extracellular matrix/PI3K-AKT pathway impair anti-tumor effect of trastuzumab. We observe CTSE functions as a cell intrinsic enhancer of chemosensitivity of docetaxel, whereas TKTL1 functions as an attenuator. Finally, we develop prognostic models with high accuracy to predict therapeutic response, further validated in an independent validation cohort. This study provides a rich resource for investigating the mechanisms and indicators of chemotherapy and targeted therapy in GC.

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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