Overcoming resistance to arginine deprivation therapy using GC7 in pleural mesothelioma

Our plain-English summary of Overcoming resistance to arginine deprivation therapy using GC7 in pleural mesothelioma, by J. Carpentier, M. Freitas, V. Morales, et al (iScience, 2025).

The study

• Authors: J. Carpentier, M. Freitas, V. Morales, K. Bianchi, J. Bomalaski, P. Szlosarek, S.A. Martin
• Journal: iScience
• Published: 2025;28(1):111525
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2024 The Authors.

In plain English

This was a laboratory study of pleural mesothelioma cell lines and mice. It did not study asbestos exposure or patients. The drug ADI-PEG20 starves cancer cells of the nutrient arginine, but some cells become resistant to it. The authors made resistant versions of two cell lines (Ju77 and MSTO) and tested six drugs that act on polyamine metabolism. GC7 showed the most consistent effect against the resistant cells. GC7 combined with ADI-PEG20 was synergistic, meaning stronger together than expected from each alone, in all six cell lines tested. With ADI-PEG20 alone, resistant Ju77 cells appeared after 6 months. With GC7 added, no resistant cells were ever seen. In mice carrying MSTO tumors, the combination reduced tumor growth compared with no drug or either drug alone (p = 0.0005). Chemical tests suggested GC7 acts by blocking the TCA cycle, an energy pathway in cells. The authors concluded the combination has therapeutic potential. They noted that how GC7 works remains unclear, and that the absence of resistant cells might reflect experimental limitations.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: experiments on mesothelioma cell lines grown in culture and as 3D spheroids, plus a mouse xenograft experiment (human tumor cells injected under the skin of mice)
• Who was studied: Human pleural mesothelioma cell lines: Ju77 (epithelioid-like), MSTO (biphasic), H28 (sarcomatoid) and H226 (epithelioid-like), plus the ADI-PEG20-resistant lines Ju77R and MSTOR derived from them. MSTO cells were also grown as tumors in adult (7 weeks old) male NOD-SCID mice; the number of mice is not given in the text.
• Exposure: No asbestos exposure was studied. The exposures were drug treatments: ADI-PEG20 (pegylated arginine deiminase), GC7 and other polyamine-targeted agents (DFMO, 4MCHA, MDL72527, DENSPM, ciclopirox), alone and in combination. In mice: vehicle (PBS), 5 IU ADI-PEG20, 10 mg/kg GC7, or both, twice weekly.
• Main results:
  • Compared with their parental cells, the resistant cells had increased ASS1 RNA: 50-fold in Ju77R and 1,000-fold in MSTOR.
  • Among the polyamine-targeted agents tested, GC7 showed the most consistent significant inhibitory effect on the ADI-PEG20-resistant cells compared with their matched sensitive cell lines.
  • In Ju77S cells, adding DFMO to ADI-PEG20 did not prevent resistance. Resistant cells emerged faster than with ADI-PEG20 alone (1.5 vs. 6 months).
  • When Ju77S cells were grown with GC7 plus ADI-PEG20, no resistant cells were observed to emerge at any of the GC7 concentrations tested.
  • The ADI-PEG20 plus GC7 combination was synergistic, by combination index, at one ADI-PEG20 dose combined with each of four GC7 doses, in all six cell lines.
  • In MSTO, MSTOR and H28 cells, the combination caused a significant increase in cell death (cytotoxicity) compared with either drug alone. With ADI-PEG20 alone, the cytotoxic fraction rose 9-fold in MSTO, 2.7-fold in MSTOR and 1.4-fold in H28 cells.
  • In mice with MSTO tumors, tumor growth was significantly reduced (p = 0.0005) by the combination compared with vehicle or either drug alone.
  • GC7 treatment significantly reduced TCA cycle metabolites (aconitate, alpha-ketoglutarate, succinate, fumarate and malate) in all cell lines tested.
  • Adding the TCA metabolites acetyl-CoA or aconitate rescued the cell killing caused by GC7 in ADI-PEG20-resistant cells. The authors took this to suggest that GC7 acts through inhibition of the TCA cycle.
• The authors' conclusion: The authors concluded that they had identified the therapeutic potential of combining ADI-PEG20 with GC7 for mesothelioma, and suggested that the combination may prevent the emergence of resistant cells.
• Limitations the authors state:
  • Because inhibiting DHS (GC7's usual target) did not overcome resistance, it remains unclear how GC7 overcomes ADI-PEG20 resistance.
  • The authors cannot rule out that the absence of resistant clones under the combination treatment was due to experimental limitations.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Chemotherapy, Mesothelioma, Pegargiminase (ADI-PEG20), Synergistic Effect.

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