The role of GSK3 and its reversal with GSK3 antagonism in everolimus resistance
| Autor: | Felix Beuschlein, Eva J. Koziolek, Gerald Spöttl, Christoph Auernhammer, Karel Pacak, Elke Tatjana Aristizabal Prada, Julian Maurer, Michael Lauseker, Jörg Schrader, Ashley Grossman, Svenja Nölting |
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| Přispěvatelé: | University of Zurich, Nölting, Svenja |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Endocrinology Diabetes and Metabolism 10265 Clinic for Endocrinology and Diabetology Antineoplastic Agents 610 Medicine & health mTORC1 Neuroendocrine tumors Article Glycogen Synthase Kinase 3 03 medical and health sciences 0302 clinical medicine Endocrinology Cell Movement Cell Line Tumor Autophagy Humans Medicine 1306 Cancer Research Everolimus Protein Kinase Inhibitors IC50 Cyclin-dependent kinase 1 business.industry Cell migration medicine.disease 1310 Endocrinology Diabetes and Metabolism 2712 Endocrinology Diabetes and Metabolism 030104 developmental biology Oncology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research 2730 Oncology business G1 phase medicine.drug |
| Zdroj: | Endocr Relat Cancer |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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