Proteomic Profiling in Colorectal Cancer: Identifying Druggable Biomarkers for Personalized Therapy

Colorectal cancer (CRC) remains a major global health challenge, with limited treatment options for advanced-stage patients. While genomic and transcriptomic analyses aid in target identification, proteomic alterations offer a more direct link to tumor biology and therapeutic opportunities. In this study, we analyzed mass spectrometry-based proteomics data from 102 primary CRC patients, including tumor and matched normal tissues, to systematically identify overexpressed, druggable therapeutic targets, with a particular focus on the patient kinome. Using the OPPTI approach, we discovered 31 kinases with notable overexpression, including 16 currently targetable by existing drugs, such as FGR, EPHA2, and PBK. Furthermore, we revealed 884 overexpressed non-kinase proteins, 253 of which are druggable, including ERAP2, FLG, and MT1H. Differential expression analysis identified 165 dysregulated kinases and 3,903 non-kinase proteins, with MET and STK3 emerging as potential candidates due to their substantial upregulation. Integrating differential expression and overexpression analyses, we highlighted a cohort of druggable targets, including EPHA2 and MET, whose inhibition has shown promising preclinical efficacy. This comprehensive proteomic study provides a resource for novel therapeutic target discovery in CRC, offering a framework for more personalized interventions through the identification of clinically actionable protein-level alterations.