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It has recently been reported that a large proportion of human malignant pleural mesothelioma (MPM) cell lines and patient tissue samples present high expression of the c-MYC oncogene. This gene drives several tumorigenic processes and is overexpressed in many cancers. Although c-MYC is a strategic target to restrain cancer processes, no drugs acting as c-MYC inhibitors are available. The novel thienotriazolodiazepine small-molecule bromodomain inhibitor OTX015/MK-8628 has shown potent antiproliferative activity accompanied by c-MYC downregulation in several tumor types. This study was designed to evaluate the growth inhibitory effect of OTX015 on patient-derived MPM473, MPM487 and MPM60 mesothelioma cell lines and its antitumor activity in three patient-derived xenograft models, MPM473, MPM487 and MPM484, comparing it with cisplatin, gemcitabine and pemetrexed, three agents which are currently used to treat MPM in the clinic. OTX015 caused a significant delay in cell growth both in vitro and in vivo. It was the most effective drug in MPM473 xenografts and showed a similar level of activity as the most efficient treatment in the other two MPM models (gemcitabine in MPM487 and cisplatin in MPM484). In vitro studies showed that OTX015 downregulated c-MYC protein levels in both MPM473 and MPM487 cell lines. Our findings represent the first evidence of promising therapeutic activity of OTX015 in mesothelioma. [ABSTRACT FROM AUTHOR]