Metabolomic Approach to Identify Potential Biomarkers in KRAS-Mutant Pancreatic Cancer Cells.

ABSTRACT

Pancreatic cancer is characterized by its high mortality rate and limited treatment options, often driven by oncogenic RAS mutations. In this study, we investigated the metabolomic profiles of pancreatic cancer cells based on their KRAS genetic status. Utilizing both KRAS-wildtype BxPC3 and KRAS-mutant PANC1 cell lines, we identified 195 metabolites differentially altered by KRAS status through untargeted metabolomics. Principal component analysis and hierarchical condition trees revealed distinct separation between KRAS-wildtype and KRAS-mutant cells. Metabolite set enrichment analysis highlighted significant pathways such as homocysteine degradation and taurine and hypotaurine metabolism. Additionally, lipid enrichment analysis identified pathways including fatty acyl glycosides and sphingoid bases. Mapping of identified metabolites to KEGG pathways identified nine significant metabolic pathways associated with KRAS status, indicating diverse metabolic alterations in pancreatic cancer cells. Furthermore, we explored the impact of TRPML1 inhibition on the metabolomic profile of KRAS-mutant pancreatic cancer cells. TRPML1 inhibition using ML-SI1 significantly altered the metabolomic profile, leading to distinct separation between vehicle-treated and ML-SI1-treated PANC1 cells. Metabolite set enrichment analysis revealed enriched pathways such as arginine and proline metabolism, and mapping to KEGG pathways identified 17 significant metabolic pathways associated with TRPML1 inhibition. Interestingly, some metabolites identified in PANC1 compared to BxPC3 were oppositely regulated by TRPML1 inhibition, suggesting their potential as biomarkers for KRAS-mutant cancer cells. Overall, our findings shed light on the distinct metabolite changes induced by both KRAS status and TRPML1 inhibition in pancreatic cancer cells, providing insights into potential therapeutic targets and biomarkers for this deadly disease.