A systems biology approach to identify key targets in KRAS/BRAF-mutated colorectal cancer

KRAS and BRAF mutations are critical oncogenic drivers in colorectal cancer (CRC), with distinct molecular and clinical implications.

To uncover genes differentially expressed between these mutations, we compared KRAS G12D- and BRAF V600E-mutated CRC cell lines. Protein-protein interaction (PPI) network construction, pathway enrichment, survival analysis, and drug target screening were performed to identify therapeutic opportunities.

Ten hub genes-TNF, IL1B, FN1, EGF, IFI44L, EPSTI1, AHR, COL20A1, CDH1, and SOX9-were identified as critical in KRAS-driven CRC. Enrichment analysis highlighted immune and inflammatory pathways, including "SARS-CoV-2 Signaling" and "Macrophage Stimulating Protein Signaling," as well as cellular processes like "Positive Regulation of PI3K Signaling". IL1B was the only hub gene significantly associated with overall survival, suggesting its role as a favorable prognostic marker. Drug screening identified selective inhibitors such as Canakinumab and Rilonacept targeting IL1B, with docking studies revealing the strongest interaction for Omeprazole with AHR, followed by Tapinarof with AHR and Donepezil with IL1B.

This study sheds light on the molecular mechanisms of KRAS-mutated CRC, emphasizing IL1B as a prognostic marker. Among the identified therapeutic agents, Omeprazole demonstrated the strongest interaction with AHR, suggesting a potential for repurposing in CRC treatment, while IL1B-targeting inhibitors such as Canakinumab emerged as selective candidates for modulating tumor-promoting inflammation. Novel genes such as EPSTI1, COL20A1, CDH1, and SOX9 warrant further investigation.