Delineation of gastric tumors with activated ERK/MAPK signaling cascades for the development of targeted therapeutics.

The ERK/MAPK signaling pathway is activated in various cancers including gastric cancer. Targeting the ERK/MAPK/MEK pathway has been considered as a promising strategy for cancer therapy. However, MEK inhibition leads to a series of resistance mechanisms due to mutations in MEK, elevated expression of RAS or RAF proteins and activation of the associated signaling pathways. In the present study, ERK/MAPK pathway specific gene signatures were identified to be highly activated in intestinal subtype gastric tumors. Inhibition of ERK/MAPK pathway with the inhibitor PD98059 in gastric cancer cell lines by in vitro signaling pathway and genome-wide expression profiling revealed the associated signaling pathways. Functional genomic investigation of the ERK/MAPK regulated genes reveals the association of ERK/MAPK pathway with E2F, Myc, SOX-2, TGF-β, OCT4 and Notch pathways in gastric cancer cells. Of these, E2F, Myc and SOX-2 pathways are activated in intestinal subtype gastric tumors and TGF-β, OCT4, Notch pathways are activated in diffuse subtype gastric tumors. Further, the mutational load of gastric tumors was found to have association and correlation with the activation pattern of ERK/MAPK pathways across gastric tumors. ERK/MAPK activation was also found to represent the EBV and MSI activated subtypes of gastric tumors. Identification of potent drug candidates inhibiting the ERK/MAPK and associated pathways would pave a way for developing the targeted therapeutics for a subset of gastric tumors with activated ERK/MAPK signaling cascade.