Primary or acquired therapy resistance is a major obstacle to the effective treatment of cancer. Resistance to apoptosis has long been thought to contribute to therapy resistance. We show here that recombinant TRAIL and CDK9 inhibition cooperate in killing cells derived from a broad range of cancers, importantly without inducing detectable adverse events. Remarkably, the combination of TRAIL with CDK9 inhibition was also highly effective on cancers resistant to both, standard-of-care chemotherapy and various targeted therapeutic approaches. Dynamic BH3 profiling revealed that, mechanistically, combining TRAIL with CDK9 inhibition induced a drastic increase in the mitochondrial priming of cancer cells. Intriguingly, this increase occurred irrespective of whether the cancer cells were sensitive or resistant to chemo- or targeted therapy. We conclude that this pro-apoptotic combination therapy has the potential to serve as a highly effective new treatment option for a variety of different cancers. Notably, this includes cancers that are resistant to currently available treatment modalities.

原发性或获得性治疗耐药是有效治疗癌症的主要障碍。长期以来，人们一直认为对细胞凋亡的抵抗会导致治疗抵抗。我们在此表明​​，重组 TRAIL 和 CDK9 抑制协同杀死来自多种癌症的细胞，重要的是不会诱导可检测到的不良事件。值得注意的是，TRAIL 与 CDK9 抑制的组合对于对标准护理化疗和各种靶向治疗方法均具有耐药性的癌症也非常有效。动态 BH3 分析表明，从机制上讲，将 TRAIL 与 CDK9 抑制相结合可诱导癌细胞线粒体启动的急剧增加。有趣的是，无论癌细胞对化疗或靶向治疗是否敏感或耐药，这种增加都会发生。我们的结论是，这种促凋亡联合疗法有潜力成为多种不同癌症的高效新治疗选择。值得注意的是，这包括对目前可用的治疗方式有抵抗力的癌症。