Related Experiment Video
Updated: Aug 8, 2025
Generation and Expansion of Primary, Malignant Pleural Mesothelioma Tumor Lines
Published on: April 21, 2022
Novel therapeutic approaches for pleural mesothelioma identified by functional ex vivo drug sensitivity testing
Hely Ollila-Raj1, Astrid Murumägi2, Teijo Pellinen2
1Department of Pulmonary Medicine, Heart and Lung Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, Finland.
Objectives:
Pleural mesothelioma (PM) is an aggressive malignancy with limited treatment options. The first-line therapy has remained unchanged for two decades and consists of pemetrexed in combination with cisplatin. Immune-checkpoint inhibitors (nivolumab plus ipilimumab) have high response rates, resulting in recent updates in treatment recommendations by the U.S. Food and Drug Administration. However, the overall benefits of combination treatment are modest, suggesting that other targeted therapy options should be investigated.
Materials And Methods:
We employed high-throughput drug sensitivity and resistance testing on five established PM cell lines using 527 cancer drugs in a 2D setting. Drugs of the greatest potential (n = 19) were selected for further testing in primary cell models derived from pleural effusions of seven PM patients.
Results:
All established and primary patient-derived PM cell models were sensitive to the mTOR inhibitor AZD8055. Furthermore, another mTOR inhibitor (temsirolimus) showed efficacy in most of the primary patient-derived cells, although a less robust effect was observed when compared with the established cell lines. Most of the established cell lines and all patient-derived primary cells exhibited sensitivity to the PI3K/mTOR/DNA-PK inhibitor LY3023414. The Chk1 inhibitor prexasertib showed activity in 4/5 (80%) of the established cell lines and in 2/7 (29%) of the patient-derived primary cell lines. The BET family inhibitor JQ1 showed activity in four patient-derived cell models and in one established cell line.
Conclusion:
mTOR and Chk1 pathways had promising results with established mesothelioma cell lines in an ex vivo setting. In patient-derived primary cells, drugs targeting mTOR pathway in particular showed efficacy. These findings may inform novel treatment strategies for PM.
Insights
New research shows mTOR inhibitors are effective against pleural mesothelioma (PM) cell lines. These findings suggest potential new targeted therapy options for this aggressive cancer.
Area of Science:
- Oncology
- Cancer Therapeutics
- Drug Discovery
Background:
- Pleural mesothelioma (PM) is an aggressive cancer with limited treatment options.
- Current first-line therapy has not changed in two decades.
- While immune-checkpoint inhibitors show promise, overall benefits are modest, necessitating investigation into other targeted therapies.
Purpose of the Study:
- To identify novel targeted therapy options for pleural mesothelioma.
- To evaluate drug sensitivity in established and patient-derived PM cell models.
Main Methods:
- High-throughput drug sensitivity and resistance testing was performed on five established PM cell lines using 527 cancer drugs.
- Promising drugs were further tested in primary cell models derived from seven PM patients.
Main Results:
- All tested PM cell models (established and patient-derived) showed sensitivity to the mTOR inhibitor AZD8055.
- The PI3K/mTOR/DNA-PK inhibitor LY3023414 was effective in most cell models.
- Other inhibitors targeting mTOR, Chk1, and BET pathways showed varying degrees of efficacy.
Conclusions:
- Targeting the mTOR pathway shows significant promise for pleural mesothelioma treatment.
- These findings may guide the development of novel therapeutic strategies for PM.
- Further investigation into mTOR and Chk1 inhibitors is warranted for PM.
