1. Synthetic Lethality Triggered by Combining Olaparib with BRCA2-Rad51 Disruptors.
- Author
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Falchi F, Giacomini E, Masini T, Boutard N, Di Ianni L, Manerba M, Farabegoli F, Rossini L, Robertson J, Minucci S, Pallavicini I, Di Stefano G, Roberti M, Pellicciari R, and Cavalli A
- Subjects
- Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, BRCA2 Protein genetics, BRCA2 Protein metabolism, Cell Line, Tumor, DNA Repair, Gene Expression Regulation, Neoplastic, Gene Silencing, Humans, Models, Molecular, Mutation, Phthalazines chemistry, Piperazines chemistry, Protein Conformation, Rad51 Recombinase metabolism, BRCA2 Protein antagonists & inhibitors, Phthalazines pharmacology, Piperazines pharmacology, Rad51 Recombinase antagonists & inhibitors
- Abstract
In BRCA2-defective cells, poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors can trigger synthetic lethality, as two independent DNA-repairing mechanisms are simultaneously impaired. Here, we have pharmacologically induced synthetic lethality, which was triggered by combining two different small organic molecules. When administered with a BRCA2-Rad51 disruptor in nonmutant cells, Olaparib showed anticancer activity comparable to that shown when administered alone in BRCA2-defective cells. This strategy could represent an innovative approach to anticancer drug discovery and could be extended to other synthetic lethality pathways.
- Published
- 2017
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