Cancers with K-Ras mutations affect millions of people every year. K- Ras mutations are required for cancer initiation in pancreatic cancers, where as in other cancers, such as lung cancer and colorectal cancer, it arises as a form of resistance to therapy. The mechanism by which this resistance occurs is still under major investigation. Cancers that harbour K-Ras mutations usually have a dismal treatment outcome.
In this study, a systems biology approach (bioinformatic, metabolomic and molecular biology) to identify altered metabolic signatures in K-Ras mutant cancers and highlighted associating metabolic dependencies. A metabolic analysis of two isogenic colorectal cell lines with and without oncogenic K-Ras showed distinct metabolic phenotypes. To understand glucose and glutamine metabolism in K-Ras mutant cell, a 13C tracer experiment on our K-Ras isogenic cell pairs was conducted. There were no specific changes to either glucose or glutamine metabolic pathways however, results showed evidence of reductive carboxylation. K-Ras mutant cells also reduced the synthesis of de novo unsaturated fatty acids compared to the K-Ras wildtype cells.
Moreover, using public transcriptional datasets, 13 distinct metabolic genes that are upregulated in K-Ras mutant cancers were identified. Only three of the 13 genes had a prognostic value highlighted in an independent pancreatic ductal adenoma carcinoma (PDAC) study. Potassium Calcium-Activated Channel Subfamily N Member 4 (KCNN4) and Inositol Polyphosphate-4- Phosphatase Type II B (INPP4B), were further studied in colorectal cancer cells harbouring K-Ras mutations; their inhibition showed reduced growth in the K- Ras mutant cells.
Overall, using a systems biology approach led to the identification of novel metabolic phenotypes and metabolic dependencies in K-Ras mutant colorectal cancer cells; this can be further exploited for prognostic use and aid in novel therapy development.