title: 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.
authors.affiliation: Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan.|Department of Gastroenterology, Faculty of Medicine, Oita University, Oita, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Hirashita
authors.affiliation: Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Tsukamoto
authors.affiliation: Division of Biomarker Discovery, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Yanagihara
authors.affiliation: Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, Oita, Japan.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Fumoto
authors.affiliation: Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Hijiya
authors.affiliation: Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan.
authors.forename: Chisato
authors.initials: C
authors.lastname: Nakada
authors.affiliation: Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Uchida
authors.affiliation: Department of Biology, Faculty of Medicine, Oita University, Oita, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Matsuura
authors.affiliation: Department of Gastroenterology, Faculty of Medicine, Oita University, Oita, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kodama
authors.affiliation: Department of Gastroenterology, Faculty of Medicine, Oita University, Oita, Japan.
authors.forename: Tadayoshi
authors.initials: T
authors.lastname: Okimoto
authors.affiliation: Department of Diagnostic Pathology, Faculty of Medicine, Oita University, Oita, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Daa
authors.affiliation: Department of Gastroenterology, Faculty of Medicine, Oita University, Oita, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Seike
authors.affiliation: Department of Microbiology, Faculty of Medicine, Oita University, Oita, Japan.
authors.forename: Hidekatsu
authors.initials: H
authors.lastname: Iha
authors.affiliation: Department of Medical Oncology and Hematology, Faculty of Medicine, Oita University, Oita, Japan.
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Shirao
authors.affiliation: Department of Gastroenterology, Faculty of Medicine, Oita University, Oita, Japan.
authors.forename: Kazunari
authors.initials: K
authors.lastname: Murakami
authors.affiliation: Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan.
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Moriyama
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D038601:Ribosomal Protein S6 / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D038601:Ribosomal Protein S6; D000076222:Mechanistic Target of Rapamycin Complex 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Gastric cancer; MEK inhibitor; mTORC1; receptor tyrosine kinase; ribosomal protein S6