Reduced phosphorylation of ribosomal protein S6 is associated with sensitivity to MEK inhibition in gastric cancer cells

Abstract

Gastric cancer (GC) is characterized by amplifications of receptor tyrosine kinases (RTK) and KRAS, therefore, targeting of the RTK/KRAS downstream pathways could help to broaden the applicability of molecular targeted therapy for GC. We assembled a panel of 48 GC cell lines and screened predictors of responsiveness to inhibition of the RAF/MEK/ERK pathway, one of the RTK/KRAS downstream pathways. We found that GC cells with MET amplification or KRAS mutation, but not amplification, tended to be sensitive to MEK inhibition. However, several cell lines without RTK/KRAS alterations also showed high sensitivity to MEK inhibition. We then focused on the phosphorylation of RTK/KRAS downstream molecules to screen for predictors’ sensitivity to MEK inhibition. We found that the phosphorylation level of mammalian target of rapamycin complex 1 (mTORC1) downstream molecules, including p70S6K, 4EBP1, and S6, was significantly associated with sensitivity to MEK inhibition in GC cells (P < 0.05), suggesting that mTORC1 activity is related to the sensitivity to MEK inhibition. Furthermore, the change in mTORC1 activity after MEK inhibition was also significantly associated with this sensitivity (P < 0.001). Among the mTORC1 downstream molecules, the change in S6 phosphorylation (pS6) showed the most significant correlation with sensitivity. Using xenograft models derived from highly sensitive and resistant cell lines, we found specific reduction of pS6 in xenografts from highly sensitive cell lines after 6 h of treatment with an MEK inhibitor. Thus, our data suggest the potential clinical applicability of an MEK inhibitor for a proportion of GC patients who could be selected on the basis of pS6 change after MEK inhibition.

Gastric Cancer Associated Genes Identified by an Integrative Analysis of Gene Expression Data

“…For example, a recent study revealed that GLTSCR2 regulates the MDM2-TP53 pathway through RPL11, playing a key role in GC progression [ 42 ]. A previous study has observed that reducing the phosphorylation of RPS6 could have an influence on the sensitivity to MEK inhibition in gastric cancer cells [ 43 ]. Another important pathway in GC is glycolysis/gluconeogenesis pathway.…”

Embedding single-cell experimental conditions to reveal manifold structure of cancer drug perturbation effects

“…Examining the cell yield of these inhibitors compared to the respective uninhibited control conditions in their respective batches, we found that the cell yield of the Cluster D inhibitors was on average 60% lower than the TGF-β-only controls (Supplementary Table 4). Based on these findings and a prior report suggesting that decreased phosphorylation of ribosomal protein S6 may be associated with sensitivity to certain targeted therapies [17], it is possible that the C-5 subtype may be relatively resistant to inhibition of the PI3K-AKT-mTOR axis.…”

S6 ribosomal protein phosphorylation is associated with malignancy of intraductal papillary mucinous neoplasm of the pancreas

“…Cell proliferation assay were performed as described previously 10 . Cells were incubated with DMSO or the serially diluted PF04691502 (0.1, 1.0, and 10 μmol/L).…”