The role of GSK3 and its reversal with GSK3 antagonism in everolimus resistance
Pancreatic neuroendocrine tumors (panNETs) are often inoperable at diagnosis. The mTORC1 inhibitor everolimus has been approved for the treatment of advanced NETs. However, the regular development of resistance to everolimus limits its clinical efficacy. We established two independent everolimus-res...
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creator | Aristizabal Prada, Elke Tatjana Spöttl, Gerald Maurer, Julian Lauseker, Michael Koziolek, Eva Jolanthe Schrader, Jörg Grossman, Ashley Pacak, Karel Beuschlein, Felix Auernhammer, Christoph Joseph Nölting, Svenja |
description | Pancreatic neuroendocrine tumors (panNETs) are often inoperable at diagnosis. The mTORC1 inhibitor everolimus has been approved for the treatment of advanced NETs. However, the regular development of resistance to everolimus limits its clinical efficacy. We established two independent everolimus-resistant panNET (BON1) cell lines (BON1 RR1, BON1 RR2) to find potential mechanisms of resistance. After 24 weeks of permanent exposure to 10 nM everolimus, BON1 RR1 and BON1 RR2 showed stable resistance with cellular survival rates of 96.70% (IC50 = 5200 nM) and 92.30% (IC50 = 2500 nM), respectively. The control cell line showed sensitivity to 10 nM everolimus with cellular survival declining to 54.70% (IC50 = 34 nM). Both resistant cell lines did not regain sensitivity over time and showed persistent stable resistance after a drug holiday of 13 weeks. The mechanisms of resistance in our cell line model included morphological adaptations, G1 cell cycle arrest associated with reduced CDK1(cdc2) expression and decreased autophagy. Cellular migration potential was increased and indirectly linked to c-Met activation. GSK3 was over-activated in association with reduced baseline IRS-1 protein levels. Specific GSK3 inhibition strongly decreased BON1 RR1/RR2 cell survival. The combination of everolimus with the PI3Kα inhibitor BYL719 re-established everolimus sensitivity through GSK3 inhibition and restoration of autophagy. We suggest that GSK3 over-activation combined with decreased baseline IRS-1 protein levels and decreased autophagy may be a crucial feature of everolimus resistance, and hence, a possible therapeutic target. |
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The mTORC1 inhibitor everolimus has been approved for the treatment of advanced NETs. However, the regular development of resistance to everolimus limits its clinical efficacy. We established two independent everolimus-resistant panNET (BON1) cell lines (BON1 RR1, BON1 RR2) to find potential mechanisms of resistance. After 24 weeks of permanent exposure to 10 nM everolimus, BON1 RR1 and BON1 RR2 showed stable resistance with cellular survival rates of 96.70% (IC50 = 5200 nM) and 92.30% (IC50 = 2500 nM), respectively. The control cell line showed sensitivity to 10 nM everolimus with cellular survival declining to 54.70% (IC50 = 34 nM). Both resistant cell lines did not regain sensitivity over time and showed persistent stable resistance after a drug holiday of 13 weeks. The mechanisms of resistance in our cell line model included morphological adaptations, G1 cell cycle arrest associated with reduced CDK1(cdc2) expression and decreased autophagy. Cellular migration potential was increased and indirectly linked to c-Met activation. GSK3 was over-activated in association with reduced baseline IRS-1 protein levels. Specific GSK3 inhibition strongly decreased BON1 RR1/RR2 cell survival. The combination of everolimus with the PI3Kα inhibitor BYL719 re-established everolimus sensitivity through GSK3 inhibition and restoration of autophagy. We suggest that GSK3 over-activation combined with decreased baseline IRS-1 protein levels and decreased autophagy may be a crucial feature of everolimus resistance, and hence, a possible therapeutic target.</description><identifier>ISSN: 1351-0088</identifier><identifier>EISSN: 1479-6821</identifier><identifier>DOI: 10.1530/ERC-18-0159</identifier><identifier>PMID: 29895527</identifier><language>eng</language><publisher>England: Bioscientifica Ltd</publisher><subject>Adaptation ; Antagonism ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Autophagy ; Autophagy - drug effects ; Cdc2 protein ; Cell cycle ; Cell Line, Tumor ; Cell Movement - drug effects ; Cell survival ; Drug Resistance, Neoplasm - drug effects ; Drug Resistance, Neoplasm - genetics ; Everolimus - pharmacology ; Everolimus - therapeutic use ; Glycogen Synthase Kinase 3 - genetics ; Humans ; Insulin receptor substrate 1 ; Neuroendocrine tumors ; Pancreas ; Phagocytosis ; Protein Kinase Inhibitors - pharmacology ; Protein Kinase Inhibitors - therapeutic use ; Therapeutic applications</subject><ispartof>Endocrine-related cancer, 2018-10, Vol.25 (10), p.893-908</ispartof><rights>2018 Society for Endocrinology</rights><rights>2018 Society for Endocrinology.</rights><rights>Copyright Society for Endocrinology & BioScientifica Ltd. Oct 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b451t-d5adaca6c49d60ff0d3af675c748004f62dd6b6d7ef7aab857ab00a1c7d49b873</citedby><cites>FETCH-LOGICAL-b451t-d5adaca6c49d60ff0d3af675c748004f62dd6b6d7ef7aab857ab00a1c7d49b873</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3936,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29895527$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Aristizabal Prada, Elke Tatjana</creatorcontrib><creatorcontrib>Spöttl, Gerald</creatorcontrib><creatorcontrib>Maurer, Julian</creatorcontrib><creatorcontrib>Lauseker, Michael</creatorcontrib><creatorcontrib>Koziolek, Eva Jolanthe</creatorcontrib><creatorcontrib>Schrader, Jörg</creatorcontrib><creatorcontrib>Grossman, Ashley</creatorcontrib><creatorcontrib>Pacak, Karel</creatorcontrib><creatorcontrib>Beuschlein, Felix</creatorcontrib><creatorcontrib>Auernhammer, Christoph Joseph</creatorcontrib><creatorcontrib>Nölting, Svenja</creatorcontrib><title>The role of GSK3 and its reversal with GSK3 antagonism in everolimus resistance</title><title>Endocrine-related cancer</title><addtitle>Endocr Relat Cancer</addtitle><description>Pancreatic neuroendocrine tumors (panNETs) are often inoperable at diagnosis. The mTORC1 inhibitor everolimus has been approved for the treatment of advanced NETs. However, the regular development of resistance to everolimus limits its clinical efficacy. We established two independent everolimus-resistant panNET (BON1) cell lines (BON1 RR1, BON1 RR2) to find potential mechanisms of resistance. After 24 weeks of permanent exposure to 10 nM everolimus, BON1 RR1 and BON1 RR2 showed stable resistance with cellular survival rates of 96.70% (IC50 = 5200 nM) and 92.30% (IC50 = 2500 nM), respectively. The control cell line showed sensitivity to 10 nM everolimus with cellular survival declining to 54.70% (IC50 = 34 nM). Both resistant cell lines did not regain sensitivity over time and showed persistent stable resistance after a drug holiday of 13 weeks. The mechanisms of resistance in our cell line model included morphological adaptations, G1 cell cycle arrest associated with reduced CDK1(cdc2) expression and decreased autophagy. Cellular migration potential was increased and indirectly linked to c-Met activation. GSK3 was over-activated in association with reduced baseline IRS-1 protein levels. Specific GSK3 inhibition strongly decreased BON1 RR1/RR2 cell survival. The combination of everolimus with the PI3Kα inhibitor BYL719 re-established everolimus sensitivity through GSK3 inhibition and restoration of autophagy. We suggest that GSK3 over-activation combined with decreased baseline IRS-1 protein levels and decreased autophagy may be a crucial feature of everolimus resistance, and hence, a possible therapeutic target.</description><subject>Adaptation</subject><subject>Antagonism</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Autophagy</subject><subject>Autophagy - drug effects</subject><subject>Cdc2 protein</subject><subject>Cell cycle</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement - drug effects</subject><subject>Cell survival</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Everolimus - pharmacology</subject><subject>Everolimus - therapeutic use</subject><subject>Glycogen Synthase Kinase 3 - genetics</subject><subject>Humans</subject><subject>Insulin receptor substrate 1</subject><subject>Neuroendocrine tumors</subject><subject>Pancreas</subject><subject>Phagocytosis</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein Kinase Inhibitors - therapeutic use</subject><subject>Therapeutic applications</subject><issn>1351-0088</issn><issn>1479-6821</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU1rFTEUhgdR7Ieu3EvAjVCmnmQmk2QjlEtbpYWC1nU4k4_elJlJTWYq_fdmuG1RFy7CCbwPD-fwVtU7CseUN_Dp9NumprIGytWLap-2QtWdZPRl-Tec1gBS7lUHOd8CQCc5f13tMSUV50zsV1fXW0dSHByJnpx_v2gITpaEOZPk7l3KOJBfYd4-RTPexCnkkYSJrHkcwrisbA55xsm4N9Urj0N2bx_nYfXj7PR686W-vDr_ujm5rPuW07m2HC0a7EyrbAfeg23Qd4Ib0UqA1nfM2q7vrHBeIPaSC-wBkBphW9VL0RxWn3feu6UfnTVumhMO-i6FEdODjhj038kUtvom3mvRNgqAFcHHR0GKPxeXZz2GbNww4OTikjUD3iouGFMF_fAPehuXNJXzNKOUlSfpKjzaUSbFnJPzz8tQ0GtRuhSlqdRrUYV-_-f-z-xTMwWgO6APMZtQrgg-GPyv9De8PJ6G</recordid><startdate>20181001</startdate><enddate>20181001</enddate><creator>Aristizabal Prada, Elke Tatjana</creator><creator>Spöttl, Gerald</creator><creator>Maurer, Julian</creator><creator>Lauseker, Michael</creator><creator>Koziolek, Eva Jolanthe</creator><creator>Schrader, Jörg</creator><creator>Grossman, Ashley</creator><creator>Pacak, Karel</creator><creator>Beuschlein, Felix</creator><creator>Auernhammer, Christoph Joseph</creator><creator>Nölting, Svenja</creator><general>Bioscientifica Ltd</general><general>Society for Endocrinology & BioScientifica Ltd</general><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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20181001</creationdate><title>The role of GSK3 and its reversal with GSK3 antagonism in everolimus resistance</title><author>Aristizabal Prada, Elke Tatjana ; Spöttl, Gerald ; Maurer, Julian ; Lauseker, Michael ; Koziolek, Eva Jolanthe ; Schrader, Jörg ; Grossman, Ashley ; Pacak, Karel ; Beuschlein, Felix ; Auernhammer, Christoph Joseph ; Nölting, Svenja</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b451t-d5adaca6c49d60ff0d3af675c748004f62dd6b6d7ef7aab857ab00a1c7d49b873</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adaptation</topic><topic>Antagonism</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Autophagy</topic><topic>Autophagy - drug effects</topic><topic>Cdc2 protein</topic><topic>Cell cycle</topic><topic>Cell Line, Tumor</topic><topic>Cell Movement - drug effects</topic><topic>Cell survival</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Drug Resistance, Neoplasm - genetics</topic><topic>Everolimus - pharmacology</topic><topic>Everolimus - therapeutic use</topic><topic>Glycogen Synthase Kinase 3 - genetics</topic><topic>Humans</topic><topic>Insulin receptor substrate 1</topic><topic>Neuroendocrine tumors</topic><topic>Pancreas</topic><topic>Phagocytosis</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein Kinase Inhibitors - therapeutic use</topic><topic>Therapeutic applications</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Aristizabal Prada, Elke Tatjana</creatorcontrib><creatorcontrib>Spöttl, Gerald</creatorcontrib><creatorcontrib>Maurer, Julian</creatorcontrib><creatorcontrib>Lauseker, Michael</creatorcontrib><creatorcontrib>Koziolek, Eva Jolanthe</creatorcontrib><creatorcontrib>Schrader, Jörg</creatorcontrib><creatorcontrib>Grossman, Ashley</creatorcontrib><creatorcontrib>Pacak, Karel</creatorcontrib><creatorcontrib>Beuschlein, Felix</creatorcontrib><creatorcontrib>Auernhammer, Christoph Joseph</creatorcontrib><creatorcontrib>Nölting, Svenja</creatorcontrib><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>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Endocrine-related cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Aristizabal Prada, Elke Tatjana</au><au>Spöttl, Gerald</au><au>Maurer, Julian</au><au>Lauseker, Michael</au><au>Koziolek, Eva Jolanthe</au><au>Schrader, Jörg</au><au>Grossman, Ashley</au><au>Pacak, Karel</au><au>Beuschlein, Felix</au><au>Auernhammer, Christoph Joseph</au><au>Nölting, Svenja</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The role of GSK3 and its reversal with GSK3 antagonism in everolimus resistance</atitle><jtitle>Endocrine-related cancer</jtitle><addtitle>Endocr Relat Cancer</addtitle><date>2018-10-01</date><risdate>2018</risdate><volume>25</volume><issue>10</issue><spage>893</spage><epage>908</epage><pages>893-908</pages><issn>1351-0088</issn><eissn>1479-6821</eissn><abstract>Pancreatic neuroendocrine tumors (panNETs) are often inoperable at diagnosis. The mTORC1 inhibitor everolimus has been approved for the treatment of advanced NETs. However, the regular development of resistance to everolimus limits its clinical efficacy. We established two independent everolimus-resistant panNET (BON1) cell lines (BON1 RR1, BON1 RR2) to find potential mechanisms of resistance. After 24 weeks of permanent exposure to 10 nM everolimus, BON1 RR1 and BON1 RR2 showed stable resistance with cellular survival rates of 96.70% (IC50 = 5200 nM) and 92.30% (IC50 = 2500 nM), respectively. The control cell line showed sensitivity to 10 nM everolimus with cellular survival declining to 54.70% (IC50 = 34 nM). Both resistant cell lines did not regain sensitivity over time and showed persistent stable resistance after a drug holiday of 13 weeks. The mechanisms of resistance in our cell line model included morphological adaptations, G1 cell cycle arrest associated with reduced CDK1(cdc2) expression and decreased autophagy. Cellular migration potential was increased and indirectly linked to c-Met activation. GSK3 was over-activated in association with reduced baseline IRS-1 protein levels. Specific GSK3 inhibition strongly decreased BON1 RR1/RR2 cell survival. The combination of everolimus with the PI3Kα inhibitor BYL719 re-established everolimus sensitivity through GSK3 inhibition and restoration of autophagy. We suggest that GSK3 over-activation combined with decreased baseline IRS-1 protein levels and decreased autophagy may be a crucial feature of everolimus resistance, and hence, a possible therapeutic target.</abstract><cop>England</cop><pub>Bioscientifica Ltd</pub><pmid>29895527</pmid><doi>10.1530/ERC-18-0159</doi><tpages>16</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Adaptation Antagonism Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Autophagy Autophagy - drug effects Cdc2 protein Cell cycle Cell Line, Tumor Cell Movement - drug effects Cell survival Drug Resistance, Neoplasm - drug effects Drug Resistance, Neoplasm - genetics Everolimus - pharmacology Everolimus - therapeutic use Glycogen Synthase Kinase 3 - genetics Humans Insulin receptor substrate 1 Neuroendocrine tumors Pancreas Phagocytosis Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - therapeutic use Therapeutic applications |
title | The role of GSK3 and its reversal with GSK3 antagonism in everolimus resistance |
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