Integrated in silico and in vitro analysis identifies putative therapeutic targets and drug candidates for malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer with poor prognosis, related to asbestos exposure. The broad molecular variation seen in MPM and its microenvironment poses a significant challenge in diagnosis, prognostics, and treatment of this devastating disease. By leveraging the patient's transcriptomic data and following a circular pattern that integrates bioinformatic analysis, wet validation, gene silencing, and functional analysis, we were able to identify three highly interesting genes that have a strong potential to be drug targets or serve as novel biomarkers for MPM: MDK, MAD2L1 and BAG2. In addition, we were able to identify two specific drugs, iMDK and Neratinib, that were effective in reducing cell proliferation in MPM cell lines. Our identification of Neratinib and iMDK as potential therapeutic options for MPM has the potential to greatly expand the list of available drugs for this disease. Neratinib, in particular, is already approved for use in breast cancer, which may facilitate its repurposing for use in MPM. The methodology employed in this study proved to be highly effective in identifying new putative targets, which is crucial in the development of targeted therapies for MPM. These findings underscore the importance of a comprehensive and iterative approach to target identification in advancing MPM treatment. In the future, it will be important to further investigate the efficacy and safety of these drugs in vivo, using mouse models of MPM. Additionally, studies aimed at elucidating the specific mechanisms of action of these drugs in the context of MPM will be necessary to optimize their use and develop effective combination therapies.