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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 ( mTORC 1) downstream molecules, including p70S6K, 4 EBP 1, and S6, was significantly associated with sensitivity to  MEK  inhibition in  GC  cells ( P  &lt; 0.05), suggesting that  mTORC 1 activity is related to the sensitivity to  MEK  inhibition. Furthermore, the change in  mTORC 1 activity after  MEK  inhibition was also significantly associated with this sensitivity ( P  &lt; 0.001). Among the  mTORC 1 downstream molecules, the change in S6 phosphorylation ( pS 6) showed the most significant correlation with sensitivity. Using xenograft models derived from highly sensitive and resistant cell lines, we found specific reduction of  pS 6 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  pS 6 change after MEK inhibition.

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