Proteome-based molecular subtyping and therapeutic target prediction in gastric cancer

Area of Science:

• Proteomics and Kinomics
• Cancer Molecular Subtyping
• Precision Oncology

Background:

• Gastric cancer (GC) molecular classification is crucial for precision treatment, but its (phospho)proteome, especially tyrosine phosphorylation, is not fully characterized.
• Existing multi-omics stratifications lack corresponding cell line models and validated therapeutic targets.
• A comprehensive characterization of GC cell line (phospho)proteomes is needed to bridge this gap.

Purpose of the Study:

• To perform a comprehensive (phospho)proteomic analysis of gastric cancer cell lines.
• To identify molecular subtypes within GC cell lines and validate therapeutic targets.
• To establish congruence between cell line and patient-derived molecular classifications.

Main Methods:

• Mass spectrometry (MS)-based (phospho)proteomic and tyrosine phosphorylation profiling of GC cell lines.
• Integrated clustering of proteomic data to identify molecular subgroups.
• Cross-validation with public patient-derived transcriptomic data and interrogation of genomic aberrations and drug sensitivity databases.

Main Results:

• Identified significant congruence between cell line proteomic and patient-derived transcriptomic subclassifications.
• Discovered casein kinase I isoform delta/epsilon (CSNK1D/E) and Src family kinases as potential therapeutic targets.
• Defined two GC cell line subtypes: EMT-subtype and metabolism-subtype, with distinct pathway enrichments and predicted targets (mTOR and MAP2K2, respectively).

Conclusions:

• This study provides novel insights into GC proteomics, kinomics, and molecular taxonomy.
• Experimental validation confirmed CSNK1D/E, mTOR, and MAP2K2 as potential therapeutic targets for specific GC subtypes.
• The findings lay the groundwork for developing precision treatments for gastric cancer based on molecular subtypes.