1. Chemical Genetic Screens Identify Kinase Inhibitor Combinations that Target Anti-Apoptotic Proteins for Cancer Therapy.
- Author
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Contreras JI, Robb CM, King HM, Baxter J, Crawford AJ, Kour S, Kizhake S, Sonawane YA, Rana S, Hollingsworth MA, Luo X, and Natarajan A
- Subjects
- Apoptosis Regulatory Proteins metabolism, Cell Line, Tumor, Doxycycline pharmacology, Drug Therapy, Combination, High-Throughput Screening Assays, Humans, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors therapeutic use, Proto-Oncogene Proteins c-bcl-2 drug effects, Proto-Oncogene Proteins c-bcl-2 metabolism, Apoptosis Regulatory Proteins drug effects, Neoplasms drug therapy, Protein Kinase Inhibitors pharmacology
- Abstract
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.
- Published
- 2018
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