4 years ago

Synthetic Lethality Triggered by Combining Olaparib with BRCA2–Rad51 Disruptors

Synthetic Lethality Triggered by Combining Olaparib with BRCA2–Rad51 Disruptors
Saverio Minucci, Janet Robertson, Elisa Giacomini, Lorenza Di Ianni, Tiziana Masini, Marcella Manerba, Marinella Roberti, Giuseppina Di Stefano, Isabella Pallavicini, Andrea Cavalli, Lara Rossini, Fulvia Farabegoli, Nicolas Boutard, Federico Falchi, Roberto Pellicciari
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.

Publisher URL: http://dx.doi.org/10.1021/acschembio.7b00707

DOI: 10.1021/acschembio.7b00707

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