AKT Inhibition Relieves Feedback Suppression of Receptor Tyrosine Kinase Expression and Activity
Activation of the PI3K-AKT pathway in tumors is modulated by negative feedback, including mTORC1-mediated inhibition of upstream signaling. We now show that AKT inhibition induces the expression and phosphorylation of multiple receptor tyrosine kinases (RTKs). In a wide spectrum of tumor types, inhi...
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| Veröffentlicht in: | Cancer cell 2011-01, Vol.19 (1), p.58-71 |
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| creator | Chandarlapaty, Sarat Sawai, Ayana Scaltriti, Maurizio Rodrik-Outmezguine, Vanessa Grbovic-Huezo, Olivera Serra, Violeta Majumder, Pradip K. Baselga, Jose Rosen, Neal |
| description | Activation of the PI3K-AKT pathway in tumors is modulated by negative feedback, including mTORC1-mediated inhibition of upstream signaling. We now show that AKT inhibition induces the expression and phosphorylation of multiple receptor tyrosine kinases (RTKs). In a wide spectrum of tumor types, inhibition of AKT induces a conserved set of RTKs, including HER3, IGF-1R, and insulin receptor. This is in part due to mTORC1 inhibition and in part secondary to a FOXO-dependent activation of receptor expression. PI3K-AKT inhibitors relieve this feedback and activate RTK signaling; this may attenuate their antitumor activity. Consistent with this model, we find that, in tumors in which AKT suppresses HER3 expression, combined inhibition of AKT and HER kinase activity is more effective than either alone.
► Inhibition of PI3K-AKT signaling in tumors activates receptor tyrosine kinases ► Induction is due to relief of feedback inhibition of FOXO-dependent RNA expression ► AKT activates feedback via FOXO- and mTORC1-dependent pathways ► Inhibition of both AKT and induced RTKs is a promising therapeutic strategy |
| doi_str_mv | 10.1016/j.ccr.2010.10.031 |
| format | Article |
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► Inhibition of PI3K-AKT signaling in tumors activates receptor tyrosine kinases ► Induction is due to relief of feedback inhibition of FOXO-dependent RNA expression ► AKT activates feedback via FOXO- and mTORC1-dependent pathways ► Inhibition of both AKT and induced RTKs is a promising therapeutic strategy</description><identifier>ISSN: 1535-6108</identifier><identifier>EISSN: 1878-3686</identifier><identifier>DOI: 10.1016/j.ccr.2010.10.031</identifier><identifier>PMID: 21215704</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Benzylamines - pharmacology ; Benzylamines - therapeutic use ; Breast Neoplasms - drug therapy ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Carcinoma, Non-Small-Cell Lung - drug therapy ; Carcinoma, Non-Small-Cell Lung - metabolism ; Carcinoma, Non-Small-Cell Lung - pathology ; Cell Line, Tumor ; Drug Therapy, Combination ; Feedback, Physiological - drug effects ; Feedback, Physiological - physiology ; Female ; Forkhead Transcription Factors - antagonists & inhibitors ; Forkhead Transcription Factors - genetics ; Forkhead Transcription Factors - metabolism ; Gefitinib ; Gene Expression - drug effects ; Gene Expression Regulation, Neoplastic - drug effects ; Gene Expression Regulation, Neoplastic - physiology ; Humans ; Lapatinib ; Mechanistic Target of Rapamycin Complex 1 ; Mice ; Mice, Nude ; Models, Biological ; Multiprotein Complexes ; Neoplasms - metabolism ; Phosphorylation - drug effects ; Promoter Regions, Genetic - genetics ; Protein Binding - drug effects ; Protein Binding - genetics ; Protein Kinase Inhibitors - pharmacology ; Protein Kinase Inhibitors - therapeutic use ; Proteins - antagonists & inhibitors ; Proto-Oncogene Proteins c-akt - antagonists & inhibitors ; Proto-Oncogene Proteins c-akt - genetics ; Proto-Oncogene Proteins c-akt - metabolism ; Quinazolines - pharmacology ; Quinazolines - therapeutic use ; Quinoxalines - pharmacology ; Quinoxalines - therapeutic use ; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors ; Receptor Protein-Tyrosine Kinases - genetics ; Receptor Protein-Tyrosine Kinases - metabolism ; Receptor, ErbB-2 - antagonists & inhibitors ; Receptor, ErbB-2 - metabolism ; Receptor, ErbB-3 - genetics ; Receptor, ErbB-3 - metabolism ; Receptor, IGF Type 1 - genetics ; Receptor, IGF Type 1 - metabolism ; Receptor, Insulin - genetics ; Receptor, Insulin - metabolism ; RNA, Small Interfering - genetics ; Signal Transduction - drug effects ; Signal Transduction - physiology ; TOR Serine-Threonine Kinases ; Up-Regulation - genetics ; Xenograft Model Antitumor Assays</subject><ispartof>Cancer cell, 2011-01, Vol.19 (1), p.58-71</ispartof><rights>2011 Elsevier Inc.</rights><rights>Copyright © 2011 Elsevier Inc. All rights reserved.</rights><rights>2010 Elsevier Inc. All rights reserved. 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c483t-ff7c9b70b0330092df6913d799c16ed3ac7129ba127bbeb798ea05305ea7b5bc3</citedby><cites>FETCH-LOGICAL-c483t-ff7c9b70b0330092df6913d799c16ed3ac7129ba127bbeb798ea05305ea7b5bc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1535610810004332$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21215704$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chandarlapaty, Sarat</creatorcontrib><creatorcontrib>Sawai, Ayana</creatorcontrib><creatorcontrib>Scaltriti, Maurizio</creatorcontrib><creatorcontrib>Rodrik-Outmezguine, Vanessa</creatorcontrib><creatorcontrib>Grbovic-Huezo, Olivera</creatorcontrib><creatorcontrib>Serra, Violeta</creatorcontrib><creatorcontrib>Majumder, Pradip K.</creatorcontrib><creatorcontrib>Baselga, Jose</creatorcontrib><creatorcontrib>Rosen, Neal</creatorcontrib><title>AKT Inhibition Relieves Feedback Suppression of Receptor Tyrosine Kinase Expression and Activity</title><title>Cancer cell</title><addtitle>Cancer Cell</addtitle><description>Activation of the PI3K-AKT pathway in tumors is modulated by negative feedback, including mTORC1-mediated inhibition of upstream signaling. We now show that AKT inhibition induces the expression and phosphorylation of multiple receptor tyrosine kinases (RTKs). In a wide spectrum of tumor types, inhibition of AKT induces a conserved set of RTKs, including HER3, IGF-1R, and insulin receptor. This is in part due to mTORC1 inhibition and in part secondary to a FOXO-dependent activation of receptor expression. PI3K-AKT inhibitors relieve this feedback and activate RTK signaling; this may attenuate their antitumor activity. Consistent with this model, we find that, in tumors in which AKT suppresses HER3 expression, combined inhibition of AKT and HER kinase activity is more effective than either alone.
► Inhibition of PI3K-AKT signaling in tumors activates receptor tyrosine kinases ► Induction is due to relief of feedback inhibition of FOXO-dependent RNA expression ► AKT activates feedback via FOXO- and mTORC1-dependent pathways ► Inhibition of both AKT and induced RTKs is a promising therapeutic strategy</description><subject>Animals</subject><subject>Benzylamines - pharmacology</subject><subject>Benzylamines - therapeutic use</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - pathology</subject><subject>Carcinoma, Non-Small-Cell Lung - drug therapy</subject><subject>Carcinoma, Non-Small-Cell Lung - metabolism</subject><subject>Carcinoma, Non-Small-Cell Lung - pathology</subject><subject>Cell Line, Tumor</subject><subject>Drug Therapy, Combination</subject><subject>Feedback, Physiological - drug effects</subject><subject>Feedback, Physiological - physiology</subject><subject>Female</subject><subject>Forkhead Transcription Factors - antagonists & inhibitors</subject><subject>Forkhead Transcription Factors - genetics</subject><subject>Forkhead Transcription Factors - metabolism</subject><subject>Gefitinib</subject><subject>Gene Expression - drug effects</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Gene Expression Regulation, Neoplastic - physiology</subject><subject>Humans</subject><subject>Lapatinib</subject><subject>Mechanistic Target of Rapamycin Complex 1</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Models, Biological</subject><subject>Multiprotein Complexes</subject><subject>Neoplasms - metabolism</subject><subject>Phosphorylation - drug effects</subject><subject>Promoter Regions, Genetic - genetics</subject><subject>Protein Binding - drug effects</subject><subject>Protein Binding - genetics</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein Kinase Inhibitors - therapeutic use</subject><subject>Proteins - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins c-akt - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins c-akt - genetics</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Quinazolines - pharmacology</subject><subject>Quinazolines - therapeutic use</subject><subject>Quinoxalines - pharmacology</subject><subject>Quinoxalines - therapeutic use</subject><subject>Receptor Protein-Tyrosine Kinases - antagonists & inhibitors</subject><subject>Receptor Protein-Tyrosine Kinases - genetics</subject><subject>Receptor Protein-Tyrosine Kinases - metabolism</subject><subject>Receptor, ErbB-2 - antagonists & inhibitors</subject><subject>Receptor, ErbB-2 - metabolism</subject><subject>Receptor, ErbB-3 - genetics</subject><subject>Receptor, ErbB-3 - metabolism</subject><subject>Receptor, IGF Type 1 - genetics</subject><subject>Receptor, IGF Type 1 - metabolism</subject><subject>Receptor, Insulin - genetics</subject><subject>Receptor, Insulin - metabolism</subject><subject>RNA, Small Interfering - genetics</subject><subject>Signal Transduction - drug effects</subject><subject>Signal Transduction - physiology</subject><subject>TOR Serine-Threonine Kinases</subject><subject>Up-Regulation - genetics</subject><subject>Xenograft Model Antitumor Assays</subject><issn>1535-6108</issn><issn>1878-3686</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUFv1DAQhS0EoqXwA7igHLlkmYnXcSIkpFXVQtVKSLCcje1MqJesHezsiv33OGxZwYWTx57vPY_mMfYSYYGA9ZvNwtq4qOD3fQEcH7FzbGRT8rqpH-dacFHWCM0Ze5bSBrIGZfuUnVVYoZCwPGdfV7fr4sbfO-MmF3zxiQZHe0rFNVFntP1efN6NY6SU5m7oM2BpnEIs1ocYkvNU3DqvExVXP0-Y9l2xspPbu-nwnD3p9ZDoxcN5wb5cX60vP5R3H9_fXK7uSrts-FT2vbStkWCAc4C26vq6Rd7JtrVYU8e1lVi1RmMljSEj24Y0CA6CtDTCWH7B3h19x53ZUmfJT1EPaoxuq-NBBe3Uvx3v7tW3sFccKgGiyQavHwxi-LGjNKmtS5aGQXsKu6RQCqygWS5nFI-ozStIkfrTNwhqTkZtVE5GzcnMTzmZrHn193wnxZ8oMvD2CFDe0t5RVMk68pY6F8lOqgvuP_a_AHh4oKE</recordid><startdate>20110118</startdate><enddate>20110118</enddate><creator>Chandarlapaty, Sarat</creator><creator>Sawai, Ayana</creator><creator>Scaltriti, Maurizio</creator><creator>Rodrik-Outmezguine, Vanessa</creator><creator>Grbovic-Huezo, Olivera</creator><creator>Serra, Violeta</creator><creator>Majumder, Pradip K.</creator><creator>Baselga, Jose</creator><creator>Rosen, Neal</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</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>7TO</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20110118</creationdate><title>AKT Inhibition Relieves Feedback Suppression of Receptor Tyrosine Kinase Expression and Activity</title><author>Chandarlapaty, Sarat ; Sawai, Ayana ; Scaltriti, Maurizio ; Rodrik-Outmezguine, Vanessa ; Grbovic-Huezo, Olivera ; Serra, Violeta ; Majumder, Pradip K. ; Baselga, Jose ; Rosen, Neal</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c483t-ff7c9b70b0330092df6913d799c16ed3ac7129ba127bbeb798ea05305ea7b5bc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Animals</topic><topic>Benzylamines - pharmacology</topic><topic>Benzylamines - therapeutic use</topic><topic>Breast Neoplasms - drug therapy</topic><topic>Breast Neoplasms - metabolism</topic><topic>Breast Neoplasms - pathology</topic><topic>Carcinoma, Non-Small-Cell Lung - drug therapy</topic><topic>Carcinoma, Non-Small-Cell Lung - metabolism</topic><topic>Carcinoma, Non-Small-Cell Lung - pathology</topic><topic>Cell Line, Tumor</topic><topic>Drug Therapy, Combination</topic><topic>Feedback, Physiological - drug effects</topic><topic>Feedback, Physiological - physiology</topic><topic>Female</topic><topic>Forkhead Transcription Factors - antagonists & inhibitors</topic><topic>Forkhead Transcription Factors - genetics</topic><topic>Forkhead Transcription Factors - metabolism</topic><topic>Gefitinib</topic><topic>Gene Expression - drug effects</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Gene Expression Regulation, Neoplastic - physiology</topic><topic>Humans</topic><topic>Lapatinib</topic><topic>Mechanistic Target of Rapamycin Complex 1</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Models, Biological</topic><topic>Multiprotein Complexes</topic><topic>Neoplasms - metabolism</topic><topic>Phosphorylation - drug effects</topic><topic>Promoter Regions, Genetic - genetics</topic><topic>Protein Binding - drug effects</topic><topic>Protein Binding - genetics</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein Kinase Inhibitors - therapeutic use</topic><topic>Proteins - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins c-akt - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins c-akt - genetics</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Quinazolines - pharmacology</topic><topic>Quinazolines - therapeutic use</topic><topic>Quinoxalines - pharmacology</topic><topic>Quinoxalines - therapeutic use</topic><topic>Receptor Protein-Tyrosine Kinases - antagonists & inhibitors</topic><topic>Receptor Protein-Tyrosine Kinases - genetics</topic><topic>Receptor Protein-Tyrosine Kinases - metabolism</topic><topic>Receptor, ErbB-2 - antagonists & inhibitors</topic><topic>Receptor, ErbB-2 - metabolism</topic><topic>Receptor, ErbB-3 - genetics</topic><topic>Receptor, ErbB-3 - metabolism</topic><topic>Receptor, IGF Type 1 - genetics</topic><topic>Receptor, IGF Type 1 - metabolism</topic><topic>Receptor, Insulin - genetics</topic><topic>Receptor, Insulin - metabolism</topic><topic>RNA, Small Interfering - genetics</topic><topic>Signal Transduction - drug effects</topic><topic>Signal Transduction - physiology</topic><topic>TOR Serine-Threonine Kinases</topic><topic>Up-Regulation - genetics</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chandarlapaty, Sarat</creatorcontrib><creatorcontrib>Sawai, Ayana</creatorcontrib><creatorcontrib>Scaltriti, Maurizio</creatorcontrib><creatorcontrib>Rodrik-Outmezguine, Vanessa</creatorcontrib><creatorcontrib>Grbovic-Huezo, Olivera</creatorcontrib><creatorcontrib>Serra, Violeta</creatorcontrib><creatorcontrib>Majumder, Pradip K.</creatorcontrib><creatorcontrib>Baselga, Jose</creatorcontrib><creatorcontrib>Rosen, Neal</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chandarlapaty, Sarat</au><au>Sawai, Ayana</au><au>Scaltriti, Maurizio</au><au>Rodrik-Outmezguine, Vanessa</au><au>Grbovic-Huezo, Olivera</au><au>Serra, Violeta</au><au>Majumder, Pradip K.</au><au>Baselga, Jose</au><au>Rosen, Neal</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>AKT Inhibition Relieves Feedback Suppression of Receptor Tyrosine Kinase Expression and Activity</atitle><jtitle>Cancer cell</jtitle><addtitle>Cancer Cell</addtitle><date>2011-01-18</date><risdate>2011</risdate><volume>19</volume><issue>1</issue><spage>58</spage><epage>71</epage><pages>58-71</pages><issn>1535-6108</issn><eissn>1878-3686</eissn><abstract>Activation of the PI3K-AKT pathway in tumors is modulated by negative feedback, including mTORC1-mediated inhibition of upstream signaling. We now show that AKT inhibition induces the expression and phosphorylation of multiple receptor tyrosine kinases (RTKs). In a wide spectrum of tumor types, inhibition of AKT induces a conserved set of RTKs, including HER3, IGF-1R, and insulin receptor. This is in part due to mTORC1 inhibition and in part secondary to a FOXO-dependent activation of receptor expression. PI3K-AKT inhibitors relieve this feedback and activate RTK signaling; this may attenuate their antitumor activity. Consistent with this model, we find that, in tumors in which AKT suppresses HER3 expression, combined inhibition of AKT and HER kinase activity is more effective than either alone.
► Inhibition of PI3K-AKT signaling in tumors activates receptor tyrosine kinases ► Induction is due to relief of feedback inhibition of FOXO-dependent RNA expression ► AKT activates feedback via FOXO- and mTORC1-dependent pathways ► Inhibition of both AKT and induced RTKs is a promising therapeutic strategy</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>21215704</pmid><doi>10.1016/j.ccr.2010.10.031</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Benzylamines - pharmacology Benzylamines - therapeutic use Breast Neoplasms - drug therapy Breast Neoplasms - metabolism Breast Neoplasms - pathology Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - metabolism Carcinoma, Non-Small-Cell Lung - pathology Cell Line, Tumor Drug Therapy, Combination Feedback, Physiological - drug effects Feedback, Physiological - physiology Female Forkhead Transcription Factors - antagonists & inhibitors Forkhead Transcription Factors - genetics Forkhead Transcription Factors - metabolism Gefitinib Gene Expression - drug effects Gene Expression Regulation, Neoplastic - drug effects Gene Expression Regulation, Neoplastic - physiology Humans Lapatinib Mechanistic Target of Rapamycin Complex 1 Mice Mice, Nude Models, Biological Multiprotein Complexes Neoplasms - metabolism Phosphorylation - drug effects Promoter Regions, Genetic - genetics Protein Binding - drug effects Protein Binding - genetics Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - therapeutic use Proteins - antagonists & inhibitors Proto-Oncogene Proteins c-akt - antagonists & inhibitors Proto-Oncogene Proteins c-akt - genetics Proto-Oncogene Proteins c-akt - metabolism Quinazolines - pharmacology Quinazolines - therapeutic use Quinoxalines - pharmacology Quinoxalines - therapeutic use Receptor Protein-Tyrosine Kinases - antagonists & inhibitors Receptor Protein-Tyrosine Kinases - genetics Receptor Protein-Tyrosine Kinases - metabolism Receptor, ErbB-2 - antagonists & inhibitors Receptor, ErbB-2 - metabolism Receptor, ErbB-3 - genetics Receptor, ErbB-3 - metabolism Receptor, IGF Type 1 - genetics Receptor, IGF Type 1 - metabolism Receptor, Insulin - genetics Receptor, Insulin - metabolism RNA, Small Interfering - genetics Signal Transduction - drug effects Signal Transduction - physiology TOR Serine-Threonine Kinases Up-Regulation - genetics Xenograft Model Antitumor Assays |
| title | AKT Inhibition Relieves Feedback Suppression of Receptor Tyrosine Kinase Expression and Activity |
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