Pharmacogenomic Characterization of a Large Cohort of Patient-Derived Cell Lines Identifies Therapeutic Strategies for Pleural Mesothelioma

Abstract Pleural mesothelioma (PM) urgently requires effective treatments. This study aimed to identify potential therapies using a drug repurposing strategy in the context of the molecular heterogeneity of PM. We performed a multiomics study of a large cohort of patient-derived primary PM cell lines (n = 58) and conducted a multistep pharmacologic study starting with a large-scale drug screen with 1,327 compounds using 11 cell lines to select drugs of interest. Integrated multiomics analysis demonstrated that the molecular landscape of the cell line cohort recapitulates the main findings in tumors and revealed important features of PM. Large-scale drug screening identified 233 active compounds belonging to recurrent therapeutic classes. Subsequent validation of 35 compounds highlighted a subset of 12 compounds performing better than standard chemotherapy, including entinostat and fluvastatin, with therapeutic activity related to molecular sarcomatoid phenotype, BAP1 mutation, and YAP/TAZ activity. Importantly, both compounds displayed the same efficacy in 2D and 3D culture models, and a single treatment with entinostat improved survival in an immunocompetent mouse model compared with fluvastatin and standard cisplatin–pemetrexed chemotherapy, which showed similar antitumor effects. Strikingly, entinostat improved the efficacy of immunotherapy based on anti-PD-1 antibody. Combination of entinostat with anti-PD-1 even eradicated tumors in several mice and immunized them against retransplantation of tumor cells. Overall, the drug sensitivity data provided by this study represent a resource to facilitate future clinical investigations to improve the treatment of PM. Significance: Pharmacogenomic characterization of a cell line biobank provides a valuable resource on drug sensitivity in mesothelioma and identifies entinostat as a promising therapeutic option, particularly in combination with immune checkpoint inhibitors.