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The role of GSK3 and its reversal with GSK3 antagonism in everolimus resistance


Aristizabal Prada, Elke Tatjana; Spoettl, Gerald; Maurer, Julian; Lauseker, Michael; Koziolek, Eva; Schrader, Jörg; Grossman, Ashley B; Pacak, Karel; Beuschlein, Felix; Auernhammer, Christoph J; Nölting, Svenja (2018). The role of GSK3 and its reversal with GSK3 antagonism in everolimus resistance. Endocrine-Related Cancer, 25(10):893-908.

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 basal 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 basal IRS-1 protein levels and decreased autophagy may be a crucial feature of everolimus resistance, and hence a possible therapeutic target.

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 basal 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 basal 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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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Endocrinology and Diabetology
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Endocrinology, Diabetes and Metabolism
Health Sciences > Oncology
Life Sciences > Endocrinology
Life Sciences > Cancer Research
Uncontrolled Keywords:Cancer Research, Oncology, Endocrinology, Diabetes and Metabolism, Endocrinology
Language:English
Date:12 June 2018
Deposited On:04 Jul 2018 13:00
Last Modified:29 Jul 2020 07:24
Publisher:European Society of Endocrinology
ISSN:1351-0088
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1530/ERC-18-0159
PubMed ID:29895527

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