Proteomic characterization of gastric cancer response to chemotherapy and targeted therapy reveals potential therapeutic strategies
Yan Li, Chen Xu, Bing Wang, Fujiang Xu, Fahan Ma, Yuanyuan Qu, Dongxian Jiang, Kai Li, Jinwen Feng, Sha Tian, Xiaohui Wu, Yunzhi Wang, Yang Liu, Zhaoyu Qin, Yalan Liu, Jing Qin, Qi Song, Xiaolei Zhang, Akesu Sujie, Jie Huang, Tianshu Liu, Kuntang Shen, Jian‐Yuan Zhao, Yingyong Hou, Chen Ding
Abstract
Chemotherapy 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.