The study presented here provides a framework for the discovery of unique inhibitor combinations that target the apoptosis network for cancer therapy. A pair of doxycycline (Dox)-inducible cell lines that specifically report on the ability of an inhibitor to induce apoptosis by targeting either the Mcl-1 arm or the Bcl-2/Bcl-xL/Bcl-w arm were used. Cell-based assays were optimized for high throughput screening (HTS) with caspase 3/7 as a read out. HTS with a 355-member kinase inhibitor library and the panel of Dox-inducible cell lines revealed that cyclin dependent kinase (CDK) inhibitors induced apoptosis by targeting the Mcl-1 arm, whereas PI3K inhibitors induced apoptosis by targeting the Bcl-2/Bcl-xL/Bcl-w arm. Validation studies identified unique combinations that synergistically inhibited growth and induced apoptosis in a panel of cancer cell lines. Since these inhibitors have been or are currently in clinical trials as single agents, the combinations can be rapidly translated to the clinics.

中文翻译：

---

化学遗传筛选确定靶向抗凋亡蛋白的激酶抑制剂组合以用于癌症治疗

这里介绍的研究提供了一个框架，用于发现针对癌症治疗的细胞凋亡网络的独特抑制剂组合。使用一对多西环素 (Dox) 诱导细胞系，这些细胞系专门报告抑制剂通过靶向 Mcl-1 臂或 Bcl-2/Bcl-xL/Bcl-w 臂诱导细胞凋亡的能力。基于细胞的测定针对高通量筛选 (HTS) 进行了优化，caspase 3/7 作为读数。具有 355 个成员的激酶抑制剂库和 Dox 诱导细胞系组的 HTS 显示细胞周期蛋白依赖性激酶 (CDK) 抑制剂通过靶向 Mcl-1 臂诱导细胞凋亡，而 PI3K 抑制剂通过靶向 Bcl-2/Bcl 诱导细胞凋亡-xL/Bcl-w 手臂。验证研究确定了在一组癌细胞系中协同抑制生长和诱导细胞凋亡的独特组合。由于这些抑制剂已经或目前正在作为单一药物进行临床试验，因此这些组合可以迅速转化为临床。