Temporal dynamics from phosphoproteomics using endoscopic biopsy specimens provides new therapeutic targets in stage IV gastric cancer

Abstract

Phosphoproteomic analysis expands our understanding of cancer biology. However, the feasibility of phosphoproteomic analysis using endoscopically collected tumor samples, especially with regards to dynamic changes upon drug treatment, remains unknown in stage IV gastric cancer. Here, we conducted a phosphoproteomic analysis using paired endoscopic biopsy specimens of pre- and post-treatment tumors (Ts) and non-tumor adjacent tissues (NATs) obtained from 4 HER2-positive gastric cancer patients who received trastuzumab-based treatment and from pre-treatment Ts and NATs of 4 HER2-negative gastric cancer patients. Our analysis identified 14,622 class 1 phosphosites with 12,749 quantified phosphosites and revealed molecular changes by HER2 positivity and treatment. An inhibitory signature of the ErbB signaling was observed in the post-treatment HER2-positive T group compared with the pre-treatment HER2-positive T group. Phosphoproteomic profiles obtained by a case-by-case review using paired pre- and post-treatment HER2-positive T could be utilized to discover predictive or resistant biomarkers. Furthermore, these data nominated therapeutic kinase targets which were exclusively activated in the patient unresponded to the treatment. The present study suggests that a phosphoproteomic analysis of endoscopic biopsy specimens provides information on dynamic molecular changes which can individually characterize biologic features upon drug treatment and identify therapeutic targets in stage IV gastric cancer.

Principles of phosphoproteomics and applications in cancer research

“…Alternatively, these temporal phosphoproteomics could pin point key signalling effectors in the acquisition of disease phenotypes and enable increasing understanding of how successful treatment leads to transition from a disease to disease-free state. As an example, an insightful study [ 146 ] used phosphoproteomics to compare kinase activation in HER2-postive gastric cancers before and after treatment with the HER2 antibody inhibitor trastuzumab. By comparing phosphoproteomic analysis of gastric cancer biopsies before and after treatment, the authors were able to gain insight into the impact of the HER2 antibody on the phosphoproteome enabling the discovery of new response biomarkers.…”

Kinase activities in pancreatic ductal adenocarcinoma with prognostic and therapeutic avenues

“…This makes phosphoproteomics a useful approach to measure the associated hyperactive pathways that could help to unravel effective drug combination strategies. Several multi-omic studies have unraveled drug vulnerabilities by exploring proteomics and phosphoproteomics in patients with colorectal [15], lung [16], esophageal [17], gastric [18], breast [19], and leukemic [20,21] tumors, and also very recently in PDAC [22][23][24][25]. A MS-based approach allows to identify and quantify phosphorylation sites in proteins that are involved in oncogenic cellular processes.…”