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Updated: Apr 11, 2026
Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics
Published on: October 2, 2014
HSP90 inhibition as a means of radiosensitizing resistant, aggressive soft tissue sarcomas
Anne Ernst1, Heike Anders1, Heidi Kapfhammer1
1Clinic for Radiotherapy and Radiation Oncology, Ludwig-Maximilians-University Munich, Munich, Germany.
Abstract:
Radiotherapy is an essential part of multi-modal treatment for soft tissue sarcomas. Treatment failure is commonly attributed to radioresistance, but comprehensive analyses of radiosensitivity are not available, and suitable biomarkers or candidates for targeted radiosensitization are scarce. Here, we systematically analyzed the intrinsic radioresistance of a panel of soft tissue sarcoma cell lines, and extracted scores of radioresistance by principal component analysis (PCA). To identify molecular markers of radioresistance, transcriptomic profiling of DNA damage response regulators was performed. The expression levels of HSP90 and its clients ATR, ATM, and NBS1 revealed strong, positive correlations with the PCA-derived radioresistance scores. Their functional involvement was addressed by HSP90 inhibition, which preferentially sensitized radioresistant sarcoma cells and was accompanied by delayed γ-H2AX foci clearance and HSP90 client protein degradation. The induction of apoptosis and necrosis was not significantly enhanced, but increased levels of basal and irradiation-induced senescence upon HSP90 inhibition were detected. Finally, evaluation of our findings in the TCGA soft tissue sarcoma cohort revealed elevated expression levels of HSP90, ATR, ATM, and NBS1 in a relevant subset of cases with particularly poor prognosis, which might preferentially benefit from HSP90 inhibition in combination with radiotherapy in the future.
Insights
Heat shock protein 90 (HSP90) inhibition can overcome radioresistance in soft tissue sarcoma cells by increasing senescence. This approach may improve radiotherapy outcomes for patients with poor-prognosis tumors expressing HSP90 and its clients.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy Research
Background:
- Radiotherapy is crucial for soft tissue sarcoma (STS) treatment, but radioresistance limits efficacy.
- Identifying biomarkers and therapeutic targets for radiosensitization remains a challenge.
Purpose of the Study:
- To systematically analyze intrinsic radioresistance in STS cell lines.
- To identify molecular markers correlated with radioresistance.
- To investigate the therapeutic potential of HSP90 inhibition in radiosensitive and radioresistant STS cells.
Main Methods:
- Principal component analysis (PCA) to derive radioresistance scores from STS cell lines.
- Transcriptomic profiling of DNA damage response regulators.
- HSP90 inhibition using chemical agents.
- Assessment of DNA damage repair (γ-H2AX foci), apoptosis, necrosis, and senescence.
- Analysis of TCGA STS cohort data.
Main Results:
- HSP90, ATR, ATM, and NBS1 expression positively correlated with PCA-derived radioresistance scores.
- HSP90 inhibition sensitized radioresistant STS cells, delaying DNA damage repair.
- HSP90 inhibition increased basal and irradiation-induced senescence, without significantly enhancing apoptosis or necrosis.
- Elevated HSP90, ATR, ATM, and NBS1 expression was found in STS cases with poor prognosis.
Conclusions:
- HSP90 and its clients (ATR, ATM, NBS1) are potential biomarkers for STS radioresistance.
- Targeting HSP90 may enhance radiotherapy efficacy by inducing senescence in radioresistant STS.
- Combined HSP90 inhibition and radiotherapy could benefit STS patients with poor-prognosis tumors.
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