Identification of oncogenic signaling pathways associated with the dimorphic metabolic dysregulations in gastric cancer subtypes

Metabolic dysregulations have been identified as intrinsic hallmarks of cancer cells. Investigations of altered metabolic processes, in the context of the associated oncogenic signaling pathways are expected to pave way for the development of targeted cancer therapeutics. We have recently identified the enrichment of glucose and glutamine metabolism in a subset of intestinal subtype gastric tumors at the level of expression of genes, gene sets and the occurrence of metabolites. On the other hand, glucose transport, glucan and fatty acid metabolism were enriched in a subset of diffuse subtype gastric tumors. In the current study, along with glucose metabolism, mTOR, HSP90, MYC, E2F, P53 and proteasome pathways were found enriched in a subset of intestinal subtype and a part of MSI subtype gastric tumors. On the other hand, along with fatty acid metabolism, the oncogenic pathway KRAS was found to be enriched in a subset of GS tumors among diffuse subtype gastric tumors. Thus, oncogenic signaling pathways associated with two distinct metabolic rewiring which differentially occurs between major gastric cancer subtypes were identified. These pathways seem the potential targets to differentially target these gastric cancer subtypes. Exploratory integrative genomic analyses reveal HSP90 inhibitors, AKT/mTOR inhibitors, and cell cycle inhibitors as potential agents to target the gastric tumors with the rewired glucose metabolism and MEK/MAPK inhibitors as suitable drug candidates to target the diffuse subtype tumors with the dysregulated fatty acid metabolism. This observation would pave way for the selective and targeted use of signaling pathway modulators for targeted and stratified gastric cancer therapeutics.

Automated summary

Metabolic dysregulation is an intrinsic hallmark of cancer cells, and investigating altered metabolic processes in the context of oncogenic signaling pathways can lead to the development of targeted cancer therapies. This study identified different oncogenic signaling pathways enriched in specific subtypes of gastric tumors, based on their metabolic rewiring. These pathways could serve as potential targets for selectively targeting different gastric cancer subtypes. The study also highlighted specific inhibitors that could be used to target gastric tumors with rewired glucose or fatty acid metabolism, paving the way for stratified and targeted gastric cancer therapeutics.