Combined quetiapine and radiation therapy approach to treat mesothelioma-initiating cells and increase survival in a mouse model of mesothelioma

Our plain-English summary of Combined quetiapine and radiation therapy approach to treat mesothelioma-initiating cells and increase survival in a mouse model of mesothelioma, by A. Cardenas, E. Arambula, L. Azizi, et al (bioRxiv, 2025).

The study

• Authors: A. Cardenas, E. Arambula, L. Azizi, T. Lam, S. Sutlief, K. Bhat, M. Saki, L. He, F. Pajonk
• Journal: bioRxiv
• Published: 2025
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: Malignant pleural mesothelioma (MPM) is a rare thoracic cancer associated with poor prognosis and low survival rates. In solid cancers, repurposed dopamine receptor antagonists have been shown to have anti-cancer effects. Moreover, in combination with radiotherapy, quetiapine (QTP), a dopamine (D) 2/3 receptor antagonist, has been shown to interfere with self-renewal capacity in glioma-initiating cells and increase survival in mouse models of glioblastoma. In this study we explore combined treatment effects in MPM.

Methods: Using mesothelioma cell lines, MSTO-211H, H2052, and H2452, and a MSTO-211H-derived orthotopic xenograft mouse model of MPM we examined how QTP combined with radiation affects mesothelioma-initiating cells (MICs) in vitro and survival in vivo. Subsequently, bulk and single cell RNA sequencing was used to characterize the transcriptomic landscape of MSTO-211H treated with combined radiation and QTP.

Results: We demonstrate that combining QTP with radiation reduces MIC self-renewal capacity and stem cell frequency. In vivo, this combination therapy significantly extends the median survival of mesothelioma-bearing mice. Clonogenic survival assays revealed that QTP does not enhance radiosensitivity in the tested mesothelioma cell lines. Sequencing data revealed, combined treatment downregulated cell cycle and proliferation pathways, depleted cancer stem cells, and increased cellular senescence.

Conclusion: Taken together, our study highlights the therapeutic potential of radiation with QTP in the treatment of MPM.

In plain English

This preprint, posted on bioRxiv and not certified by peer review, was a laboratory and mouse study of malignant pleural mesothelioma. It did not study asbestos exposure. The authors tested quetiapine, a drug that blocks dopamine receptors, combined with radiation. In three human mesothelioma cell lines (MSTO-211H, H2052 and H2452), 10 µM quetiapine plus 4 Gy radiation significantly reduced sphere formation and the estimated frequency of stem-like cells. Quetiapine did not make cells more sensitive to radiation in colony-forming tests. In immunodeficient mice carrying MSTO-211H tumors in the chest (9 to 13 mice per group), one 10 Gy radiation dose plus quetiapine 30 mg/kg significantly improved median survival compared with all other groups. The figure lists 73.5 for the combination against 52.5 (control), 51 (radiation alone) and 52.5 (quetiapine alone), with no units stated. Neither treatment alone significantly improved survival. Gene-activity tests showed reduced cell-cycle and stem-cell signals and higher senescence scores. The authors concluded that the combination could represent a promising approach and that further studies are warranted.

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: Preprint (not peer reviewed) laboratory study: experiments on human mesothelioma cell lines, an animal experiment in mice with implanted human tumors, and bulk and single-cell RNA sequencing
• Who was studied: Three commercially purchased human mesothelioma cell lines: MSTO-211H (biphasic), NCI-H2052 (epithelial) and NCI-H2452 (epithelial). Also immunodeficient NSG mice with MSTO-211H cells injected into the chest cavity, 9 to 13 mice per group, at UCLA. Dates were not given.
• Exposure: Treatment, not asbestos. In cells: quetiapine 10 µM with or without radiation (0 or 4 Gy; 2 to 8 Gy in colony tests). In mice: quetiapine 30 mg/kg injected under the skin on a 5-days-on, 2-days-off schedule, and/or a single 10 Gy dose to the chest on day 8 after tumor implantation. Controls received saline or sham irradiation.
• Main results:
  • In all three cell lines, sphere-forming capacity was significantly lower in the combination-treated groups than in controls.
  • Combined quetiapine and radiation significantly decreased estimated stem cell frequencies in all cell lines tested.
  • In colony-forming (clonogenic) assays, quetiapine produced no reduction in surviving fraction after 2, 4, 6 or 8 Gy in the three cell lines. The authors read this as quetiapine not enhancing the response to radiation.
  • In tumor-bearing mice, combined radiation and quetiapine significantly improved median survival compared with all other groups. Radiation alone and quetiapine alone did not significantly improve survival.
  • The figure's table lists median survival, with no units given, as 52.5 for 0 Gy plus saline, 51 for 10 Gy plus saline, 52.5 for 0 Gy plus quetiapine, and 73.5 for 10 Gy plus quetiapine.
  • Mouse weights were not affected by daily quetiapine treatment or by the combined treatment.
  • In MSTO-211H stem-like cells, the combination upregulated 298 genes relative to untreated control and 395 genes relative to radiation alone. It downregulated 436 and 912 genes relative to the same two groups.
  • Compared with control, the combination significantly downregulated genes targeted by the E2F, SOX2 and NANOG transcription factors.
  • In single-cell sequencing, senescence scores were significantly higher in the quetiapine and quetiapine-plus-radiation groups than in the control and radiation-alone groups.
• The authors' conclusion: The authors concluded that adding quetiapine to existing treatments could represent a promising approach to improving outcomes in malignant pleural mesothelioma. They said further preclinical and clinical studies are warranted.
• Limitations the authors state:
  • There was no well-defined mesothelioma reference dataset for labeling cell types in the single-cell sequencing.
  • The study used the commercially available biphasic cell line MSTO-211H rather than patient-derived models or cell lines from other histological subtypes.
  • Sequencing was done on cells grown in suspension without serum, whereas earlier studies mainly used attached (adherent) cells.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleural Mesothelioma, Prognosis, STEM, Median Overall Survival.

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