Repurposing drug screen of patient-derived malignant pleural mesothelioma cells reveals potential anti-cancer activity

Malignant pleural mesothelioma (MPM) has a very poor prognosis: 50% of the patients die within 12 months after starting first-line treatment and no improvement of survival has been reached with second-line treatment. To date, data available on drug screening for mesothelioma is very limited and was only performed using established cell lines. We previously showed that these cell lines have a highly different transcriptomic profile when compared to fresh tumors while patient-derived cell lines most closely resemble the profile of the corresponding cancers. Patient-derived cell lines were generated from digested fresh tumor specimens and characterised by RNA sequencing, whole exome sequencing and histological analysis. A cell viability assay was established for four patient-derived cell lines and a healthy control. A drug screen using a set of 6’500 chemical compounds including Food and Drug Administration (FDA)-approved drugs and candidates in clinical development was performed. Approximately 1000 molecules were considered as hits during the primary screen and dose response curves were performed using 120 selected hits based on viability inhibition potential, previous data on inactivity in mesothelioma and approval status of drugs. A final selection of promising drugs was made after this screen for testing on additional cell lines to understand their mode of action. Calculating dose response curves revealed 11 promising drugs to be repurposed in mesothelioma including anthelmintics, antibiotics, statins, CDC-, HDAC- and NF-kB inhibitors with IC50 s being significantly lower in malignant cell lines compared to healthy cells. To validate the viability inhibiting potential of these drugs, 21 additional MPM cell lines were screened and revealed Regorafenib, Rigosertinib and NSC663284 as most potent candidates for further inVitro and inVivo analysis. Here, we could demonstrate that a high-throughput drug repurposing screen can be an effective tool to find new treatment candidates for MPM. Currently, further validation of the three promising drug candidates is ongoing and will reveal the full potential of repurposing drugs in mesothelioma.