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

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.

Potential of Copper and Copper Compounds for Anticancer Applications

“…Due to the lack of apparent symptoms in the early stage, gastric cancer patients are generally detected late. About 80% of gastric cancer patients are diagnosed in the middle and advanced stages, which is very difficult to treat [ 57 ]. Most clinical treatment is based on surgery, supplemented by radiotherapy and chemotherapy.…”

Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

“…Abnormal kinase activity and expression are implicated in various types of cancers. In recent years, with the increasing development of mass spectrometry (MS) technology, the Clinical Proteomic Tumor Analysis Consortium and many other teams have conducted phosphoproteomics investigations in various cancers, such as lung cancer, 139 , 140 , 141 , 142 colorectal cancer (CRC), 143 , 144 , 145 , 146 liver cancer, 147 breast cancer, 148 prostate cancer, 149 gastric cancer, 150 , 151 head and neck cancer, 152 esophageal cancer, 153 pancreatic cancer (PC), 154 , 155 kidney cancer, 156 , 157 melanoma, 158 skin cancer, 159 leukemia, 160 pancreatic ductal adenocarcinoma (PDAC), 161 pituitary neuroendocrine tumors, 162 cholangiocarcinoma, 163 and urothelial carcinoma of the bladder. 164 …”

Tumour‐associated macrophages in gastric cancer: From function and mechanism to application

“…Thus, different types of TAMs usually indicate different prognoses and therapeutic responses in patients with GC (Table 4). 161,162 Li et al reported that high infiltration of M1 TAMs (IL-18) not only positively correlated with the microsatellite instable/microsatellite stable (MSI/MSS)-sig but also predicted better OS in GC patients with stage IV (94 samples) by using proteomic analysis. 162 Su et al found that patients with high infiltration of macrophages (CD68) were often related to poor response to neoadjuvant chemotherapy in a 103 sample cohort.…”

“…161,162 Li et al reported that high infiltration of M1 TAMs (IL-18) not only positively correlated with the microsatellite instable/microsatellite stable (MSI/MSS)-sig but also predicted better OS in GC patients with stage IV (94 samples) by using proteomic analysis. 162 Su et al found that patients with high infiltration of macrophages (CD68) were often related to poor response to neoadjuvant chemotherapy in a 103 sample cohort. 41 Meanwhile, high infiltration of M2 TAMs (CD206) was usually forecasted as resistant to trastuzumab therapy in patients with HER2-positive GC.…”