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.
Falchi, F., Giacomini, E., Masini, T., Boutard, N., Di Ianni, L., Manerba, M., et al. (2017). Synthetic Lethality Triggered by Combining Olaparib with BRCA2-Rad51 Disruptors. ACS CHEMICAL BIOLOGY, 12(10), 2491-2497 [10.1021/acschembio.7b00707].
Synthetic Lethality Triggered by Combining Olaparib with BRCA2-Rad51 Disruptors
Falchi, Federico;Giacomini, Elisa;Di Ianni, Lorenza;Manerba, Marcella;Farabegoli, Fulvia;Di Stefano, Giuseppina;Roberti, Marinella;Cavalli, Andrea
2017
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
