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Overcoming resistance to arginine deprivation therapy using GC7 in pleural mesothelioma
Josephine Carpentier1, Marta Freitas1, Valle Morales1
1Centre for Cancer Cell & Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
Abstract:
Pleural mesothelioma is a highly chemotherapy-resistant cancer. Approximately 50% of mesotheliomas do not express argininosuccinate synthetase 1 (ASS1), the rate-limiting enzyme in arginine biosynthesis, making arginine depletion with pegylated arginine deiminase (ADI-PEG20) an attractive therapeutic strategy. We investigated whether combinatory treatment composed of ADI-PEG20 and polyamine inhibitors constitutes a promising novel therapeutic strategy to overcome ADI-PEG20 resistance in mesothelioma patients. Treatment of ADI-PEG20-resistant cell lines with a range of different polyamine inhibitors demonstrated that ADI-PEG20-resistant cell lines were highly sensitive to the spermidine-analog GC7. We observed a synergistic effect of GC7 and ADI-PEG20 in both ADI-PEG20-sensitive and ADI-PEG20-resistant cell lines. Metabolomic analysis revealed that sensitivity to GC7 is due to inhibition of the Tricarboxylic (TCA) cycle. Significantly, combination of GC7 and ADI-PEG20 prevented the emergence of resistant cells in vitro. Taken together, we have identified the therapeutic potential of combinatorial treatment of ADI-PEG20 with GC7 for mesothelioma management.
Insights
Combining pegylated arginine deiminase (ADI-PEG20) with spermidine-analog GC7 shows promise for treating chemotherapy-resistant mesothelioma. This novel combination therapy, targeting arginine biosynthesis and the TCA cycle, overcomes resistance and prevents cancer cell adaptation.
Area of Science:
- Oncology
- Biochemistry
- Cancer Therapeutics
Background:
- Pleural mesothelioma exhibits high resistance to conventional chemotherapy.
- Argininosuccinate synthetase 1 (ASS1) deficiency in 50% of mesotheliomas presents a therapeutic vulnerability.
- Arginine depletion using pegylated arginine deiminase (ADI-PEG20) is a potential treatment strategy.
Purpose of the Study:
- To evaluate the efficacy of combining ADI-PEG20 with polyamine inhibitors.
- To investigate a novel therapeutic strategy for overcoming ADI-PEG20 resistance in mesothelioma.
- To identify potential synergistic effects and mechanisms of action.
Main Methods:
- Treatment of ADI-PEG20-resistant mesothelioma cell lines with polyamine inhibitors.
- Assessment of sensitivity to the spermidine-analog GC7.
- Evaluation of synergistic effects of combined ADI-PEG20 and GC7 treatment.
- Metabolomic analysis to elucidate mechanisms of action.
- In vitro assessment of resistance emergence with combination therapy.
Main Results:
- ADI-PEG20-resistant mesothelioma cells demonstrated high sensitivity to GC7.
- A synergistic anti-cancer effect was observed with the combination of GC7 and ADI-PEG20 in both sensitive and resistant cell lines.
- Metabolomic analysis indicated that GC7 sensitivity is linked to Tricarboxylic Acid (TCA) cycle inhibition.
- The combination of GC7 and ADI-PEG20 effectively prevented the emergence of resistant mesothelioma cells in vitro.
Conclusions:
- The combination of ADI-PEG20 and GC7 represents a promising therapeutic strategy for mesothelioma.
- This novel approach targets both arginine biosynthesis and the TCA cycle to overcome chemotherapy resistance.
- Further investigation into this combination therapy is warranted for mesothelioma management.
