Potent pro-apoptotic combination therapy is highly effective in a broad range of cancers.
Potent pro-apoptotic combination therapy is highly effective in a broad range of cancers.
复制标题
在广泛的癌症中，有效的促凋亡组合疗法非常有效。
DOI：
10.1038/s41418-021-00869-x
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发表时间：
2022-03
影响因子：
12.4
通讯作者：
Walczak H
中科院分区：
文献类型：
--
作者：
Montinaro A;Areso Zubiaur I;Saggau J;Kretz AL;Ferreira RMM;Hassan O;Kitzig E;Müller I;El-Bahrawy MA;von Karstedt S;Kulms D;Liccardi G;Lemke J;Walczak H
原发性或获得性治疗抗性是有效治疗癌症的主要障碍。对细胞凋亡的抗性长期以来被认为是导致治疗抗性的原因。我们在这里表明，重组TRAIL和CDK9抑制合作杀死细胞来源于广泛的癌症，重要的是不诱导可检测的不良事件。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都具有抗性的癌症也非常有效。动态BH3谱显示，从机制上讲，TRAIL与CDK9抑制的组合诱导了癌细胞线粒体启动的急剧增加。有趣的是，无论癌细胞是否对化疗或靶向治疗敏感或耐药，这种增加都会发生。我们的结论是，这种促凋亡联合治疗有可能作为一种高效的新的治疗选择，用于各种不同的癌症。值得注意的是，这包括对目前可用的治疗方式具有抗性的癌症。
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.
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DOI：
10.1038/s41577-019-0218-4
发表时间：
2020-01
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Kalbasi A;Ribas A
通讯作者：
Ribas A
影响因子：
12.4
作者：
Adams JM;Cory S
通讯作者：
Cory S
影响因子：
13.5
作者：
Ganten, TM;Koschny, R;Walczak, H
通讯作者：
Walczak, H
影响因子：
82.9
作者：
Kondo, T;Suda, T;Nagata, S
通讯作者：
Nagata, S
影响因子：
8.8
作者：
Fox JL;MacFarlane M
通讯作者：
MacFarlane M