恶性胸膜间皮瘤（MPM）是一种侵袭性癌症，预后不良，迫切需要鉴定新的药物靶点。在之前的工作中，我们鉴定了 15 个在 MPM 组织中高表达且与不良预后相关的失调基因。在这里，我们在 211 名 MPM 患者的独立数据集（EGA，EGAD00001001915）和一组 MPM 细胞系上验证了这些发现。此外，我们进行了体外基因沉默，然后进行增殖、细胞毒性、半胱天冬酶和迁移测定，以确定这些靶标是否可能是癌症驱动基因。我们最终得到了三种新的候选药物（即 BAG2、MAD2L1 和 MDK），它们编码的蛋白质可以用作药物靶标。此外，新颖的是，组织的免疫组织化学分析表明，BAG2 和 MAD2L1 的过度表达可以区分 MPM 和 RMP 患者。此外，当我们测试 Neratinib（MAD2L1 抑制剂）和 iMDK（MDK 抑制剂）时，我们发现它们对 MPM 细胞有效，部分表现出 MAD2L1 和 MDK 基因沉默的影响。总之，在目前的工作中，我们报告 BAG2、MAD2L1 和 MDK 是 MPM 值得进一步研究的真正癌症驱动基因。© 2024。作者。

Malignant pleural mesothelioma (MPM) is an aggressive cancer with a poor prognosis and the identification of novel druggable targets is urgently needed. In previous work, we identified 15 deregulated genes highly expressed in MPM tissues and correlated with a poor prognosis. Here, we validated these findings on an independent dataset of 211 MPM patients (EGA, EGAD00001001915) and on a panel of MPM cell lines. Furthermore, we carried out in vitro gene silencing followed by proliferation, cytotoxicity, caspase, and migration assays to define whether these targets could be cancer-driver genes. We ended up with three novel candidates (i.e., BAG2, MAD2L1, and MDK), whose encoded proteins could be exploited as druggable targets. Moreover, of novelty, immunohistochemistry analysis on tissues revealed that the overexpression of BAG2 and MAD2L1 could differentiate MPM from RMP patients. Furthermore, when we tested Neratinib (an inhibitor of MAD2L1) and iMDK (an inhibitor of MDK) we found that they are effective on MPM cells, in part phenocopying the effects of MAD2L1 and MDK gene silencing. In summary, in the present work, we report that BAG2, MAD2L1, and MDK are bona fide cancer-driver genes for MPM worth of further studies.© 2024. The Author(s).