Reduced phosphorylation of ribosomal protein S6 is associated with sensitivity to MEK inhibition in gastric cancer cells.
Reduced phosphorylation of ribosomal protein S6 is associated with sensitivity to MEK inhibition in gastric cancer cells.
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DOI：
10.1111/cas.13094
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发表时间：
2016-12
期刊：
影响因子：
5.7
通讯作者：
Moriyama M
中科院分区：
文献类型：
--
作者：
Hirashita Y;Tsukamoto Y;Yanagihara K;Fumoto S;Hijiya N;Nakada C;Uchida T;Matsuura K;Kodama M;Okimoto T;Daa T;Seike M;Iha H;Shirao K;Murakami K;Moriyama M
胃癌的特点是受体酪氨酸激酶(RTK)和KRAS的扩增，因此靶向RTK/KRAS下游通路有助于拓宽分子靶向治疗胃癌的应用范围。我们组装了一个由48个GC细胞株组成的小组，并筛选出对抑制RAF/MEK/ERK途径的反应性的预测因子，RAF/MEK/ERK途径是RTK/KRAS下游途径之一。我们发现，具有MET扩增或KRAS突变而不是扩增的GC细胞倾向于对MEK抑制敏感。然而，几个RTK/KRAS未改变的细胞株对MEK抑制也表现出很高的敏感性。然后，我们重点研究了RTK/KRAS下游分子的磷酸化，以筛选预测因子对MEK抑制的敏感性。我们发现哺乳动物靶分子雷帕霉素复合体1(MTORC1)下游分子p70S6K、4EBP1和S6的磷酸化水平与胃癌细胞对MEK抑制的敏感性显著相关(P<；0.05)，提示mTORC1的活性与对MEK抑制的敏感性有关。此外，MEK抑制后mTORC 1活性的变化也与这种敏感性显著相关(P<；0.001)。在mTORC1下游分子中，S6磷酸化(PS6)的变化与敏感性的相关性最强。使用来自高敏感和耐药细胞系的异种移植模型，我们发现高敏感细胞系的异种移植瘤在用MEK抑制剂处理6h后pS6特异性减少。因此，我们的数据提示了MEK抑制剂对部分GC患者的潜在临床适用性，这些患者可以根据MEK抑制后pS6的变化进行选择。
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.
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影响因子：
24.5
作者：
Deng N;Goh LK;Wang H;Das K;Tao J;Tan IB;Zhang S;Lee M;Wu J;Lim KH;Lei Z;Goh G;Lim QY;Tan AL;Sin Poh DY;Riahi S;Bell S;Shi MM;Linnartz R;Zhu F;Yeoh KG;Toh HC;Yong WP;Cheong HC;Rha SY;Boussioutas A;Grabsch H;Rozen S;Tan P
通讯作者：
Tan P
影响因子：
158.5
作者：
Druker, Brian J.;Guilhot, Francois;Larson, Richard A.
通讯作者：
Larson, Richard A.
DOI：
10.1006/bbrc.2001.5216
发表时间：
2001-07-20
影响因子：
3.1
作者：
Moriyama, M;Tsukamoto, Y;Ito, H
通讯作者：
Ito, H
影响因子：
17.1
作者：
Corcoran RB;Rothenberg SM;Hata AN;Faber AC;Piris A;Nazarian RM;Brown RD;Godfrey JT;Winokur D;Walsh J;Mino-Kenudson M;Maheswaran S;Settleman J;Wargo JA;Flaherty KT;Haber DA;Engelman JA
通讯作者：
Engelman JA
影响因子：
7.4
作者：
Narahara, Hiroyuki;Iishi, Hiroyasu;Imamura, Hiroshi;Tsuburaya, Akira;Chin, Keisho;Imamoto, Haruhiko;Esaki, Taito;Furukawa, Hiroshi;Hamada, Chikuma;Sakata, Yuh
通讯作者：
Sakata, Yuh