Open AccessSynthetic Lethality Triggered by Combining Olaparib with BRCA2–Rad51 Disruptors
Author(s) -
Federico Falchi,
Elisa Giacomini,
Tiziana Masini,
Nicolas Boutard,
Lorenza Di Ianni,
Marcella Manerba,
Fulvia Farabegoli,
Lara Rossini,
Janet Robertson,
Saverio Minucci,
Isabella Pallavicini,
Giuseppina Di Stefano,
Marinella Roberti,
Roberto Pellicciari,
Andrea Cavalli
Publication year - 2017
Publication title -
acs chemical biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.899
H-Index - 111
eISSN - 1554-8937
pISSN - 1554-8929
DOI - 10.1021/acschembio.7b00707
Subject(s) - olaparib , synthetic lethality , lethality , rad51 , brca2 protein , biology , poly adp ribose polymerase , microbiology and biotechnology , cancer research , computational biology , chemistry , dna damage , genetics , dna repair , mutation , dna , polymerase , gene , germline mutation
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.
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