PRMT5 Inhibition as a Potential Strategy for KRAS Mutant CRC: Downstream Mediators of the PRMT5–KRAS Crosstalk

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide with KRAS mutations present in nearly 45% of cases. Compared to KRAS wild-type (WT) CRC, KRAS-mutant CRC is associated with poorer prognosis and fewer effective treatment options. Protein Arginine Methyltransferase 5 (PRMT5), an epigenetic regulator involved in diverse cellular processes, is currently under investigation as a therapeutic target in multiple cancer types. Our previous work demonstrated that PRMT5 inhibition produces stronger therapeutic effects in KRAS-mutant CRC cells than in KRAS WT cells, suggesting potential crosstalk between PRMT5 and KRAS. In this study, we aimed to identify key downstream proteins that may mediate this interaction. Through a literature review, protein–protein interaction analysis (STRING database), gene expression analysis (GEPIA database), and correlation analysis (GEPIA database), we identified MYC, E2F1, and EIF4E as critical candidates. These proteins are shown to interact with both PRMT5 and KRAS in STRING, are overexpressed in CRC tumor samples, and show positive gene expression correlations with PRMT5 and KRAS in patient data. These findings are significant, as they provide new insights into the PRMT5–KRAS crosstalk and suggest potential targets for novel and combination therapies in KRAS-mutant CRC. Further research and biological experiments are needed to verify and outline the exact molecular processes behind MYC, E2F1, and EIF4E’s interactions with both PRMT5 and KRAS.