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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Veröffentlicht in:Endocrine-related cancer 2018-10, Vol.25 (10), p.893-908
Hauptverfasser: 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
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container_end_page 908
container_issue 10
container_start_page 893
container_title Endocrine-related cancer
container_volume 25
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.
doi_str_mv 10.1530/ERC-18-0159
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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. 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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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