Reduced phosphorylation of ribosomal protein S6 is associated with sensitivity to MEK inhibition in gastric cancer cells
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...
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| Veröffentlicht in: | Cancer science 2016-12, Vol.107 (12), p.1919-1928 |
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| creator | Hirashita, Yuka Tsukamoto, Yoshiyuki Yanagihara, Kazuyoshi Fumoto, Shoichi Hijiya, Naoki Nakada, Chisato Uchida, Tomohisa Matsuura, Keiko Kodama, Masaaki Okimoto, Tadayoshi Daa, Tsutomu Seike, Masataka Iha, Hidekatsu Shirao, Kuniaki Murakami, Kazunari Moriyama, Masatsugu |
| description | 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 is genetically so heterogeneous that particular genomic alterations is not valid for the prediction of sensitivity to molecular targeting drugs. In this study, we propose a new concept that would allow patients to be selected on the basis of the phosphorylation level of signaling molecules and targeting of a common pathway downstream from various types of genomic alterations. |
| doi_str_mv | 10.1111/cas.13094 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5198963</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2290171141</sourcerecordid><originalsourceid>FETCH-LOGICAL-c5004-5a8995060d259c88cde37b78e6ae286b0d5cbcab9071205d492ed323f6504a413</originalsourceid><addsrcrecordid>eNp1kV1rFDEUhoMotlYv_AMS8KZeTJvvTG6EstQPrAhWr0Mmk-2mzCZrTqZ1_73pbi0qGAg5kOc8nMOL0EtKTmg7p97BCeXEiEfokHJhOk2IeryrdWcIZwfoGcA1IVwJI56iA6aVMUb0h-jn1zDOPox4s8rQbtlOrsaccF7iEocMee0mvCm5hpjwpcIRsAPIPrraum5jXWEICWKNN7Fucc348_knHNMqDnEnam1XDmqJHnuXfCjYh2mC5-jJ0k0QXty_R-j7u_Nviw_dxZf3HxdnF52XhIhOut4YSRQZmTS-7_0YuB50H5QLrFcDGaUfvBsM0ZQROQrDwsgZXypJhBOUH6G3e-9mHtZh9CHV4ia7KXHtytZmF-3fPymu7FW-sZKa3ijeBMf3gpJ_zAGqXUe4W8GlkGewtJdGGK2pbOjrf9DrPJfU1rOMGUI1pbuJ3uwpXzJACcuHYSixd3nalqfd5dnYV39O_0D-DrABp3vgNk5h-3-TXZxd7pW_AEzgq74</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2290171141</pqid></control><display><type>article</type><title>Reduced phosphorylation of ribosomal protein S6 is associated with sensitivity to MEK inhibition in gastric cancer cells</title><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>Access via Wiley Online Library</source><source>Wiley Online Library (Open Access Collection)</source><source>PubMed Central</source><creator>Hirashita, Yuka ; Tsukamoto, Yoshiyuki ; Yanagihara, Kazuyoshi ; Fumoto, Shoichi ; Hijiya, Naoki ; Nakada, Chisato ; Uchida, Tomohisa ; Matsuura, Keiko ; Kodama, Masaaki ; Okimoto, Tadayoshi ; Daa, Tsutomu ; Seike, Masataka ; Iha, Hidekatsu ; Shirao, Kuniaki ; Murakami, Kazunari ; Moriyama, Masatsugu</creator><creatorcontrib>Hirashita, Yuka ; Tsukamoto, Yoshiyuki ; Yanagihara, Kazuyoshi ; Fumoto, Shoichi ; Hijiya, Naoki ; Nakada, Chisato ; Uchida, Tomohisa ; Matsuura, Keiko ; Kodama, Masaaki ; Okimoto, Tadayoshi ; Daa, Tsutomu ; Seike, Masataka ; Iha, Hidekatsu ; Shirao, Kuniaki ; Murakami, Kazunari ; Moriyama, Masatsugu</creatorcontrib><description>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 is genetically so heterogeneous that particular genomic alterations is not valid for the prediction of sensitivity to molecular targeting drugs. In this study, we propose a new concept that would allow patients to be selected on the basis of the phosphorylation level of signaling molecules and targeting of a common pathway downstream from various types of genomic alterations.</description><identifier>ISSN: 1347-9032</identifier><identifier>EISSN: 1349-7006</identifier><identifier>DOI: 10.1111/cas.13094</identifier><identifier>PMID: 27699948</identifier><language>eng</language><publisher>England: John Wiley & Sons, Inc</publisher><subject>Animals ; Cancer therapies ; Cell Line, Tumor ; Chemotherapy ; Cytotoxicity ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Resistance, Neoplasm - drug effects ; Drug Resistance, Neoplasm - genetics ; Drugs ; Extracellular signal-regulated kinase ; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors ; Extracellular Signal-Regulated MAP Kinases - metabolism ; Gastric cancer ; Gene Expression ; Humans ; K-Ras protein ; Kinases ; Laboratories ; Mechanistic Target of Rapamycin Complex 1 ; Medical prognosis ; MEK inhibitor ; MEK inhibitors ; Melanoma ; Metabolic pathways ; Mice ; mTORC1 ; Multiprotein Complexes - metabolism ; Original ; Phosphorylation ; Protein Kinase Inhibitors - pharmacology ; Proteins ; Raf protein ; Rapamycin ; receptor tyrosine kinase ; Ribosomal protein S6 ; Ribosomal Protein S6 - metabolism ; Ribosomal Protein S6 Kinases, 70-kDa - genetics ; Ribosomal Protein S6 Kinases, 70-kDa - metabolism ; Signal Transduction - drug effects ; Stomach Neoplasms - genetics ; Stomach Neoplasms - metabolism ; Stomach Neoplasms - pathology ; TOR protein ; TOR Serine-Threonine Kinases - metabolism ; Tyrosine ; Xenograft Model Antitumor Assays ; Xenografts</subject><ispartof>Cancer science, 2016-12, Vol.107 (12), p.1919-1928</ispartof><rights>2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.</rights><rights>Copyright John Wiley & Sons, Inc. 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5004-5a8995060d259c88cde37b78e6ae286b0d5cbcab9071205d492ed323f6504a413</citedby><cites>FETCH-LOGICAL-c5004-5a8995060d259c88cde37b78e6ae286b0d5cbcab9071205d492ed323f6504a413</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5198963/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5198963/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,1417,11562,27924,27925,45574,45575,46052,46476,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27699948$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hirashita, Yuka</creatorcontrib><creatorcontrib>Tsukamoto, Yoshiyuki</creatorcontrib><creatorcontrib>Yanagihara, Kazuyoshi</creatorcontrib><creatorcontrib>Fumoto, Shoichi</creatorcontrib><creatorcontrib>Hijiya, Naoki</creatorcontrib><creatorcontrib>Nakada, Chisato</creatorcontrib><creatorcontrib>Uchida, Tomohisa</creatorcontrib><creatorcontrib>Matsuura, Keiko</creatorcontrib><creatorcontrib>Kodama, Masaaki</creatorcontrib><creatorcontrib>Okimoto, Tadayoshi</creatorcontrib><creatorcontrib>Daa, Tsutomu</creatorcontrib><creatorcontrib>Seike, Masataka</creatorcontrib><creatorcontrib>Iha, Hidekatsu</creatorcontrib><creatorcontrib>Shirao, Kuniaki</creatorcontrib><creatorcontrib>Murakami, Kazunari</creatorcontrib><creatorcontrib>Moriyama, Masatsugu</creatorcontrib><title>Reduced phosphorylation of ribosomal protein S6 is associated with sensitivity to MEK inhibition in gastric cancer cells</title><title>Cancer science</title><addtitle>Cancer Sci</addtitle><description>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 is genetically so heterogeneous that particular genomic alterations is not valid for the prediction of sensitivity to molecular targeting drugs. In this study, we propose a new concept that would allow patients to be selected on the basis of the phosphorylation level of signaling molecules and targeting of a common pathway downstream from various types of genomic alterations.</description><subject>Animals</subject><subject>Cancer therapies</subject><subject>Cell Line, Tumor</subject><subject>Chemotherapy</subject><subject>Cytotoxicity</subject><subject>Disease Models, Animal</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Drugs</subject><subject>Extracellular signal-regulated kinase</subject><subject>Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors</subject><subject>Extracellular Signal-Regulated MAP Kinases - metabolism</subject><subject>Gastric cancer</subject><subject>Gene Expression</subject><subject>Humans</subject><subject>K-Ras protein</subject><subject>Kinases</subject><subject>Laboratories</subject><subject>Mechanistic Target of Rapamycin Complex 1</subject><subject>Medical prognosis</subject><subject>MEK inhibitor</subject><subject>MEK inhibitors</subject><subject>Melanoma</subject><subject>Metabolic pathways</subject><subject>Mice</subject><subject>mTORC1</subject><subject>Multiprotein Complexes - metabolism</subject><subject>Original</subject><subject>Phosphorylation</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Proteins</subject><subject>Raf protein</subject><subject>Rapamycin</subject><subject>receptor tyrosine kinase</subject><subject>Ribosomal protein S6</subject><subject>Ribosomal Protein S6 - metabolism</subject><subject>Ribosomal Protein S6 Kinases, 70-kDa - genetics</subject><subject>Ribosomal Protein S6 Kinases, 70-kDa - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>Stomach Neoplasms - genetics</subject><subject>Stomach Neoplasms - metabolism</subject><subject>Stomach Neoplasms - pathology</subject><subject>TOR protein</subject><subject>TOR Serine-Threonine Kinases - metabolism</subject><subject>Tyrosine</subject><subject>Xenograft Model Antitumor Assays</subject><subject>Xenografts</subject><issn>1347-9032</issn><issn>1349-7006</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp1kV1rFDEUhoMotlYv_AMS8KZeTJvvTG6EstQPrAhWr0Mmk-2mzCZrTqZ1_73pbi0qGAg5kOc8nMOL0EtKTmg7p97BCeXEiEfokHJhOk2IeryrdWcIZwfoGcA1IVwJI56iA6aVMUb0h-jn1zDOPox4s8rQbtlOrsaccF7iEocMee0mvCm5hpjwpcIRsAPIPrraum5jXWEICWKNN7Fucc348_knHNMqDnEnam1XDmqJHnuXfCjYh2mC5-jJ0k0QXty_R-j7u_Nviw_dxZf3HxdnF52XhIhOut4YSRQZmTS-7_0YuB50H5QLrFcDGaUfvBsM0ZQROQrDwsgZXypJhBOUH6G3e-9mHtZh9CHV4ia7KXHtytZmF-3fPymu7FW-sZKa3ijeBMf3gpJ_zAGqXUe4W8GlkGewtJdGGK2pbOjrf9DrPJfU1rOMGUI1pbuJ3uwpXzJACcuHYSixd3nalqfd5dnYV39O_0D-DrABp3vgNk5h-3-TXZxd7pW_AEzgq74</recordid><startdate>201612</startdate><enddate>201612</enddate><creator>Hirashita, Yuka</creator><creator>Tsukamoto, Yoshiyuki</creator><creator>Yanagihara, Kazuyoshi</creator><creator>Fumoto, Shoichi</creator><creator>Hijiya, Naoki</creator><creator>Nakada, Chisato</creator><creator>Uchida, Tomohisa</creator><creator>Matsuura, Keiko</creator><creator>Kodama, Masaaki</creator><creator>Okimoto, Tadayoshi</creator><creator>Daa, Tsutomu</creator><creator>Seike, Masataka</creator><creator>Iha, Hidekatsu</creator><creator>Shirao, Kuniaki</creator><creator>Murakami, Kazunari</creator><creator>Moriyama, Masatsugu</creator><general>John Wiley & Sons, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>8FE</scope><scope>8FH</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7TO</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>201612</creationdate><title>Reduced phosphorylation of ribosomal protein S6 is associated with sensitivity to MEK inhibition in gastric cancer cells</title><author>Hirashita, Yuka ; Tsukamoto, Yoshiyuki ; Yanagihara, Kazuyoshi ; Fumoto, Shoichi ; Hijiya, Naoki ; Nakada, Chisato ; Uchida, Tomohisa ; Matsuura, Keiko ; Kodama, Masaaki ; Okimoto, Tadayoshi ; Daa, Tsutomu ; Seike, Masataka ; Iha, Hidekatsu ; Shirao, Kuniaki ; Murakami, Kazunari ; Moriyama, Masatsugu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5004-5a8995060d259c88cde37b78e6ae286b0d5cbcab9071205d492ed323f6504a413</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Cancer therapies</topic><topic>Cell Line, Tumor</topic><topic>Chemotherapy</topic><topic>Cytotoxicity</topic><topic>Disease Models, Animal</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Drug Resistance, Neoplasm - genetics</topic><topic>Drugs</topic><topic>Extracellular signal-regulated kinase</topic><topic>Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors</topic><topic>Extracellular Signal-Regulated MAP Kinases - metabolism</topic><topic>Gastric cancer</topic><topic>Gene Expression</topic><topic>Humans</topic><topic>K-Ras protein</topic><topic>Kinases</topic><topic>Laboratories</topic><topic>Mechanistic Target of Rapamycin Complex 1</topic><topic>Medical prognosis</topic><topic>MEK inhibitor</topic><topic>MEK inhibitors</topic><topic>Melanoma</topic><topic>Metabolic pathways</topic><topic>Mice</topic><topic>mTORC1</topic><topic>Multiprotein Complexes - metabolism</topic><topic>Original</topic><topic>Phosphorylation</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Proteins</topic><topic>Raf protein</topic><topic>Rapamycin</topic><topic>receptor tyrosine kinase</topic><topic>Ribosomal protein S6</topic><topic>Ribosomal Protein S6 - metabolism</topic><topic>Ribosomal Protein S6 Kinases, 70-kDa - genetics</topic><topic>Ribosomal Protein S6 Kinases, 70-kDa - metabolism</topic><topic>Signal Transduction - drug effects</topic><topic>Stomach Neoplasms - genetics</topic><topic>Stomach Neoplasms - metabolism</topic><topic>Stomach Neoplasms - pathology</topic><topic>TOR protein</topic><topic>TOR Serine-Threonine Kinases - metabolism</topic><topic>Tyrosine</topic><topic>Xenograft Model Antitumor Assays</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hirashita, Yuka</creatorcontrib><creatorcontrib>Tsukamoto, Yoshiyuki</creatorcontrib><creatorcontrib>Yanagihara, Kazuyoshi</creatorcontrib><creatorcontrib>Fumoto, Shoichi</creatorcontrib><creatorcontrib>Hijiya, Naoki</creatorcontrib><creatorcontrib>Nakada, Chisato</creatorcontrib><creatorcontrib>Uchida, Tomohisa</creatorcontrib><creatorcontrib>Matsuura, Keiko</creatorcontrib><creatorcontrib>Kodama, Masaaki</creatorcontrib><creatorcontrib>Okimoto, Tadayoshi</creatorcontrib><creatorcontrib>Daa, Tsutomu</creatorcontrib><creatorcontrib>Seike, Masataka</creatorcontrib><creatorcontrib>Iha, Hidekatsu</creatorcontrib><creatorcontrib>Shirao, Kuniaki</creatorcontrib><creatorcontrib>Murakami, Kazunari</creatorcontrib><creatorcontrib>Moriyama, Masatsugu</creatorcontrib><collection>Wiley Online Library (Open Access Collection)</collection><collection>Wiley Free Content</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Biological Science Database</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hirashita, Yuka</au><au>Tsukamoto, Yoshiyuki</au><au>Yanagihara, Kazuyoshi</au><au>Fumoto, Shoichi</au><au>Hijiya, Naoki</au><au>Nakada, Chisato</au><au>Uchida, Tomohisa</au><au>Matsuura, Keiko</au><au>Kodama, Masaaki</au><au>Okimoto, Tadayoshi</au><au>Daa, Tsutomu</au><au>Seike, Masataka</au><au>Iha, Hidekatsu</au><au>Shirao, Kuniaki</au><au>Murakami, Kazunari</au><au>Moriyama, Masatsugu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Reduced phosphorylation of ribosomal protein S6 is associated with sensitivity to MEK inhibition in gastric cancer cells</atitle><jtitle>Cancer science</jtitle><addtitle>Cancer Sci</addtitle><date>2016-12</date><risdate>2016</risdate><volume>107</volume><issue>12</issue><spage>1919</spage><epage>1928</epage><pages>1919-1928</pages><issn>1347-9032</issn><eissn>1349-7006</eissn><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 is genetically so heterogeneous that particular genomic alterations is not valid for the prediction of sensitivity to molecular targeting drugs. In this study, we propose a new concept that would allow patients to be selected on the basis of the phosphorylation level of signaling molecules and targeting of a common pathway downstream from various types of genomic alterations.</abstract><cop>England</cop><pub>John Wiley & Sons, Inc</pub><pmid>27699948</pmid><doi>10.1111/cas.13094</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Cancer science, 2016-12, Vol.107 (12), p.1919-1928 |
| issn | 1347-9032 1349-7006 |
| language | eng |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Access via Wiley Online Library; Wiley Online Library (Open Access Collection); PubMed Central |
| subjects | Animals Cancer therapies Cell Line, Tumor Chemotherapy Cytotoxicity Disease Models, Animal Dose-Response Relationship, Drug Drug Resistance, Neoplasm - drug effects Drug Resistance, Neoplasm - genetics Drugs Extracellular signal-regulated kinase Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors Extracellular Signal-Regulated MAP Kinases - metabolism Gastric cancer Gene Expression Humans K-Ras protein Kinases Laboratories Mechanistic Target of Rapamycin Complex 1 Medical prognosis MEK inhibitor MEK inhibitors Melanoma Metabolic pathways Mice mTORC1 Multiprotein Complexes - metabolism Original Phosphorylation Protein Kinase Inhibitors - pharmacology Proteins Raf protein Rapamycin receptor tyrosine kinase Ribosomal protein S6 Ribosomal Protein S6 - metabolism Ribosomal Protein S6 Kinases, 70-kDa - genetics Ribosomal Protein S6 Kinases, 70-kDa - metabolism Signal Transduction - drug effects Stomach Neoplasms - genetics Stomach Neoplasms - metabolism Stomach Neoplasms - pathology TOR protein TOR Serine-Threonine Kinases - metabolism Tyrosine Xenograft Model Antitumor Assays Xenografts |
| title | Reduced phosphorylation of ribosomal protein S6 is associated with sensitivity to MEK inhibition in gastric cancer cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-21T03%3A15%3A33IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Reduced%20phosphorylation%20of%20ribosomal%20protein%20S6%20is%20associated%20with%20sensitivity%20to%20MEK%20inhibition%20in%20gastric%20cancer%20cells&rft.jtitle=Cancer%20science&rft.au=Hirashita,%20Yuka&rft.date=2016-12&rft.volume=107&rft.issue=12&rft.spage=1919&rft.epage=1928&rft.pages=1919-1928&rft.issn=1347-9032&rft.eissn=1349-7006&rft_id=info:doi/10.1111/cas.13094&rft_dat=%3Cproquest_pubme%3E2290171141%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2290171141&rft_id=info:pmid/27699948&rfr_iscdi=true |