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Updated: Nov 12, 2025
Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics
Published on: October 2, 2014
Cooperative treatment effectiveness of ATR and HSP90 inhibition in Ewing's sarcoma cells
Christian Marx1, Marc U Schaarschmidt2,3, Joanna Kirkpatrick1,4
1Leibniz Institute On Aging - Fritz Lipmann Institute (FLI), Jena, Germany.
Introduction:
Ewing's sarcoma is an aggressive childhood malignancy whose outcome has not substantially improved over the last two decades. In this study, combination treatments of the HSP90 inhibitor AUY922 with either the ATR inhibitor VE821 or the ATM inhibitor KU55933 were investigated for their effectiveness in Ewing's sarcoma cells.
Methods:
Effects were determined in p53 wild-type and p53 null Ewing's sarcoma cell lines by flow cytometric analyses of cell death, mitochondrial depolarization and cell-cycle distribution as well as fluorescence and transmission electron microscopy. They were molecularly characterized by gene and protein expression profiling, and by quantitative whole proteome analysis.
Results:
AUY922 alone induced DNA damage, apoptosis and ER stress, while reducing the abundance of DNA repair proteins. The combination of AUY922 with VE821 led to strong apoptosis induction independent of the cellular p53 status, yet based on different molecular mechanisms. p53 wild-type cells activated pro-apoptotic gene transcription and underwent mitochondria-mediated apoptosis, while p53 null cells accumulated higher levels of DNA damage, ER stress and autophagy, eventually leading to apoptosis. Impaired PI3K/AKT/mTOR signaling further contributed to the antineoplastic combination effects of AUY922 and VE821. In contrast, the combination of AUY922 with KU55933 did not produce a cooperative effect.
Conclusion:
Our study reveals that HSP90 and ATR inhibitor combination treatment may be an effective therapeutic approach for Ewing's sarcoma irrespective of the p53 status.
Insights
Combination therapy with HSP90 inhibitor AUY922 and ATR inhibitor VE821 shows promise for treating Ewing's sarcoma. This approach effectively induces cancer cell death regardless of p53 status, offering a potential new treatment strategy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Ewing's sarcoma is a challenging childhood cancer with limited treatment advancements.
- Investigating novel therapeutic strategies is crucial for improving patient outcomes.
Purpose of the Study:
- To evaluate the efficacy of combining HSP90 inhibitor AUY922 with ATR inhibitor VE821 or ATM inhibitor KU55933 in Ewing's sarcoma cells.
- To understand the molecular mechanisms underlying combination treatment effects.
Main Methods:
- Utilized p53 wild-type and p53 null Ewing's sarcoma cell lines.
- Assessed cell death, mitochondrial depolarization, and cell-cycle distribution via flow cytometry.
- Performed gene/protein expression profiling and quantitative whole proteome analysis.
Main Results:
- AUY922 alone induced DNA damage, apoptosis, and ER stress.
- The combination of AUY922 and VE821 strongly induced apoptosis, irrespective of p53 status, through distinct mechanisms in p53 wild-type and null cells.
- AUY922 and KU55933 combination did not show synergistic effects.
- Impaired PI3K/AKT/mTOR signaling contributed to the anti-cancer effects of AUY922 and VE821.
Conclusions:
- Combination therapy with HSP90 and ATR inhibitors presents a potential therapeutic strategy for Ewing's sarcoma.
- This approach may be effective regardless of the patient's p53 mutational status.
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