Despite having one of the lowest survival rates of all cancers, there have been no new approved treatments for malignant pleural mesothelioma (MPM) in over a decade. Standard-of-care treatment relies on Cisplatin plus Pemetrexed chemotherapy. Here, we tested a suite of BH3-mimetic drugs targeting BCL-2 pro-survival proteins of the intrinsic apoptotic pathway. We found BCL-XL is the dominant pro-survival protein in a panel of cell lines in vitro, though potent, synergistic cell killing occurred with MCL-1 co-targeting. This correlates with high-level expression of BCL-XL and MCL-1 in cell lines and a large cohort of patient tumour samples. BCL-XL inhibition combined with Cisplatin also enhanced cell killing. In vivo BCL-XL inhibition was as effective as Cisplatin, and the combination enhanced tumour growth control and survival. Genetic ablation of MCL-1 also enhanced the effects of BCL-XL inhibitors, in vivo. Combined, these data provide a compelling rationale for the clinical investigation of BH3-mimetics targeting BCL-XL in MPM.

尽管是所有癌症中存活率最低的癌症之一，但十多年来没有新批准的恶性胸膜间皮瘤 (MPM) 治疗方法。标准治疗依赖于顺铂加培美曲塞化疗。在这里，我们测试了一套 BH3 模拟药物，靶向内在凋亡途径的 BCL-2 促存活蛋白。我们发现 BCL-XL 是一组体外细胞系中的主要促存活蛋白，尽管 MCL-1 共靶向发生了有效的协同细胞杀伤。这与 BCL-XL 和 MCL-1 在细胞系和大量患者肿瘤样本中的高水平表达相关。BCL-XL 抑制结合顺铂也增强了细胞杀伤。体内 BCL-XL 抑制与顺铂一样有效，并且该组合增强了肿瘤生长控制和存活率。MCL-1 的基因消融也增强了 BCL-XL 抑制剂的体内作用。综合起来，这些数据为 MPM 中靶向 BCL-XL 的 BH3 模拟物的临床研究提供了令人信服的理由。