Novel therapeutic approaches for pleural mesothelioma identified by functional ex vivo drug sensitivity testing

by Selleckchem | Jul 28 2023

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.

Comments:

Summary: This study aimed to investigate potential targeted therapy options for pleural mesothelioma (PM), an aggressive malignancy with limited treatment options. The researchers conducted high-throughput drug sensitivity and resistance testing on established PM cell lines and primary cell models derived from pleural effusions of PM patients.

The results showed that the mTOR inhibitor AZD8055 was effective in both established and primary patient-derived PM cell models. Another mTOR inhibitor, temsirolimus, also demonstrated efficacy, although to a lesser extent in primary cells compared to established cell lines. The PI3K/mTOR/DNA-PK inhibitor LY3023414 showed sensitivity in most of the established cell lines and all patient-derived primary cells. The Chk1 inhibitor prexasertib exhibited activity in a majority of established cell lines and a subset of patient-derived primary cells. The BET family inhibitor JQ1 showed activity in a few patient-derived cell models and one established cell line.

Overall, the mTOR and Chk1 pathways showed promising results in established mesothelioma cell lines in an ex vivo setting. In patient-derived primary cells, drugs targeting the mTOR pathway, in particular, demonstrated efficacy. These findings suggest that targeting these pathways may be a potential strategy for novel treatment approaches in PM.

It is important to note that this study was conducted in a laboratory setting using cell models, and further research is needed to validate the effectiveness of these targeted therapies in clinical trials with PM patients.