With the development of potent and selective inhibitors of MCL-1 (S63845) and BCL-XL (A-1331852) novel cancer treatment options have emerged. BCL-2 family proteins are important regulators of apoptosis in pediatric solid tumors. In the current study, we discover that rhabdomyosarcoma, Ewing sarcoma, osteosarcoma and neuroblastoma cell lines are co-dependent on BCL-XL and MCL-1 for survival. A-1331852/S63845 co-treatment, but not combinations of either inhibitor with ABT-199, synergistically induces rapid intrinsic apoptosis in vitro and demonstrates efficiency in an in vivo embryonic chicken model of rhabdomyosarcoma. Interestingly, A-1331852/S63845-induced apoptosis is BAX/BAK-dependent and mediated by displacement of BAK from BCL-XL and MCL-1, respectively. Moreover, BAK interacts with BAX to build a pore-forming complex in the outer mitochondrial membrane, leading to loss of mitochondrial outer membrane potential and caspase activation. Furthermore, in RD cells A-1331852/S63845 co-treatment disrupts BIM and NOXA in their interactions with BCL-XL and MCL-1, respectively, thereby contributing to apoptosis. Altogether, this study is the first to demonstrate the potency of A-1331852/S63845 in pediatric solid tumor cells and to describe the molecular mechanisms of A-1331852/S63845 co-treatment underlining the potential of BCL-XL and MCL-1 inhibition as treatment regime.

中文翻译：

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针对小儿癌症中的BCL-2蛋白：BCL-XL和MCL-1的双重抑制导致内在凋亡的快速诱导。

随着MCL-1（S63845）和BCL-XL（A-1331852）的有效和选择性抑制剂的出现，出现了新的癌症治疗选择。BCL-2家族蛋白是小儿实体瘤细胞凋亡的重要调节剂。在当前的研究中，我们发现横纹肌肉瘤，尤因肉瘤，骨肉瘤和神经母细胞瘤细胞系共同依赖于BCL-XL和MCL-1的存活。A-1331852 / S63845共同处理可协同诱导体外快速内在凋亡，但在横纹肌肉瘤的体内胚胎鸡模型中却能协同诱导快速固有凋亡。有趣的是，A-1331852 / S63845诱导的凋亡是BAX / BAK依赖性的，并且分别由BAK从BCL-XL和MCL-1的取代介导。此外，BAK与BAX相互作用，在线粒体外膜上形成孔形成复合物，从而导致线粒体外膜电位的丧失和胱天蛋白酶的活化。此外，在RD细胞中，A-1331852 / S63845共同处理分别破坏了BIM和NOXA与BCL-XL和MCL-1的相互作用，从而促进了细胞凋亡。总而言之，这项研究首次证明了A-1331852 / S63845在儿科实体瘤细胞中的效力，并描述了A-1331852 / S63845联合治疗的分子机制，强调了BCL-XL和MCL-1抑制的潜力。治疗方案。从而导致细胞凋亡。总而言之，这项研究首次证明了A-1331852 / S63845在儿科实体瘤细胞中的效力，并描述了A-1331852 / S63845联合治疗的分子机制，强调了BCL-XL和MCL-1抑制的潜力。治疗方案。从而导致细胞凋亡。总而言之，这项研究首次证明了A-1331852 / S63845在儿科实体瘤细胞中的效力，并描述了A-1331852 / S63845联合治疗的分子机制，强调了BCL-XL和MCL-1抑制的潜力。治疗方案。