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Updated: Sep 29, 2025
Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics
Published on: October 2, 2014
Different HSP90 Inhibitors Exert Divergent Effect on Myxoid Liposarcoma In Vitro and In Vivo
Christoffer Vannas1,2, Lisa Andersson1, Soheila Dolatabadi1
1Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-405 30 Gothenburg, Sweden.
Abstract:
The therapeutic options for patients with relapsed or metastatic myxoid liposarcoma (MLS) remain scarce and there is currently no targeted therapy available. Inhibition of the HSP90 family of chaperones has been suggested as a possible therapeutic option for patients with MLS. However, the clinical effect of different HSP90 inhibitors vary considerably and no comparative study in MLS has been performed. Here, we evaluated the effects of the HSP90 inhibitors 17-DMAG, AUY922 and STA-9090 on MLS cell lines and in an MLS patient-derived xenograft (PDX) model. Albeit all drugs inhibited in vitro growth of MLS cell lines, the in vivo responses were discrepant. Whereas 17-DMAG inhibited tumor growth, AUY922 surprisingly led to increased tumor growth and a more aggressive morphological phenotype. In vitro, 17-DMAG and STA-9090 reduced the activity of the MAPK and PI3K/AKT signaling pathways, whereas AUY922 led to a compensatory upregulation of downstream ERK. Furthermore, all three tested HSP90 inhibitors displayed a synergistic combination effect with trabectidin, but not with doxorubicin. In conclusion, our results indicate that different HSP90 inhibitors, albeit having the same target, can vary significantly in downstream effects and treatment outcomes. These results should be considered before proceeding into clinical trials against MLS or other malignancies.
Insights
Different HSP90 inhibitors show varied efficacy in treating myxoid liposarcoma (MLS). While some reduced tumor growth, one unexpectedly increased it, highlighting the need for careful selection in clinical trials.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Therapeutic options for relapsed or metastatic myxoid liposarcoma (MLS) are limited, with no targeted therapies currently available.
- Heat shock protein 90 (HSP90) inhibition is a potential therapeutic strategy for MLS, but clinical effects of different inhibitors vary.
- No comparative studies on HSP90 inhibitors in MLS have been conducted.
Purpose of the Study:
- To evaluate the efficacy of three HSP90 inhibitors (17-DMAG, AUY922, STA-9090) in MLS.
- To compare their effects on MLS cell lines and a patient-derived xenograft (PDX) model.
- To investigate their impact on key signaling pathways and combination effects with standard chemotherapeutics.
Main Methods:
- In vitro assessment of MLS cell line growth inhibition by 17-DMAG, AUY922, and STA-9090.
- In vivo evaluation using an MLS patient-derived xenograft (PDX) model.
- Analysis of MAPK and PI3K/AKT signaling pathway activity and downstream effects.
- Combination studies with trabectidin and doxorubicin.
Main Results:
- All tested HSP90 inhibitors reduced in vitro MLS cell growth.
- In vivo, 17-DMAG inhibited tumor growth, while AUY922 paradoxically increased tumor growth and aggressiveness.
- 17-DMAG and STA-9090 decreased MAPK and PI3K/AKT signaling, whereas AUY922 caused ERK upregulation.
- All inhibitors showed synergy with trabectidin but not doxorubicin.
Conclusions:
- HSP90 inhibitors exhibit significantly different downstream effects and treatment outcomes in MLS, despite targeting the same protein.
- The choice of HSP90 inhibitor is critical and requires careful consideration before clinical application in MLS and other cancers.
- These findings underscore the importance of preclinical comparative studies to guide therapeutic strategies.
