Proteomic study reveals new drug targets in gastric signet ring cell carcinoma

Gastric signet ring cell carcinoma (GSRCC) is a distinct subtype of gastric cancer (GC) with unique epidemiological and pathogenic characteristics. Despite its clinical significance, large-scale proteomic studies on GSRCC remain scarce, limiting our molecular understanding of the disease. Advanced mass spectrometry (MS)-based proteomics is crucial for identifying key biomarkers and drug targets, thereby enabling more effective therapeutic strategies.

In a recent study published in Genes & Diseases, researchers from several institutions, including Tianjin University, Chinese Academy of Sciences, Zhejiang Cancer Hospital, Fudan University, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Chinese Academy of Medical Sciences and Peking Union Medical College, and University of Houston, characterizes the proteomic features and molecular mechanisms of GSRCC to date.

Initially, the research team analyzed clinical data from over 10,000 patients with GC between January 2010 and December 2019. An in-depth proteomic analysis was conducted on tumor tissues from 112 GSRCC patients, each with over 70% signet ring cell content. Using advanced MS, the team identified 7322 proteins, establishing the largest tissue-specific peptide spectral library for GSRCC. Additionally, through unsupervised clustering, the team identified four novel proteomic subtypes of GSRCC: Metabolism (S-Mb), Microenvironment Dysregulation (S-Me), Migration (S-M) and Proliferation (S-PF).

Two key prognostic biomarkers were identified and validated in an independent cohort of 75 patients: PRDX2, a protein associated with favorable prognosis; and DDX27, linked to poor survival outcomes. Furthermore, proteomic profiling of 79 biomarker-negative GSRCC cases revealed marked tumor heterogeneity. Notably, unsupervised clustering identified three distinct proteomic clusters, with cluster 2 linked to the poorest prognosis.

Focusing on HER2-negative, EBV-negative, and pMMR GSRCC cases (LMT [Lack of Medical Treatment]-GSRCC), the study identified four potential drug targets: eukaryotic translation initiation factor 2 subunit gamma (EIF2S3), eukaryotic translation initiation factor 6 (EIF6), and nuclear factor kappa B subunit 2 (NFKB2). Remarkably, high expression of these proteins was associated with poor prognosis, underscoring their relevance as promising therapeutic candidates.

Interestingly, molecular docking and cytotoxicity testing singled out neratinib-a drug approved for breast cancer treatment-as the most promising candidate. Furthermore, in vitro and in vivo studies demonstrated neratinib's potent ability to inhibit tumor growth, cell migration, and invasion, while promoting cancer cell apoptosis, all with minimal side effects.

In conclusion, this is the first study to focus specifically on the LMT-GSRCC population, uncovering potential biomarkers and drug targets through proteomic analysis. The findings from this study not only provide a foundation for developing novel targeted therapies but also personalized treatment strategies for GSRCC.