In:
Cancer Science, Wiley, Vol. 107, No. 12 ( 2016-12), p. 1919-1928
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 ( mTORC 1) downstream molecules, including p70S6K, 4 EBP 1, and S6, was significantly associated with sensitivity to MEK inhibition in GC cells ( P 〈 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 〈 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.
Type of Medium:
Online Resource
ISSN:
1347-9032
,
1349-7006
DOI:
10.1111/cas.2016.107.issue-12
Language:
English
Publisher:
Wiley
Publication Date:
2016
detail.hit.zdb_id:
2115647-5
detail.hit.zdb_id:
2111204-6
Permalink