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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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BRCA2 Protein / antagonists & inhibitors*
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BRCA2 Protein / genetics
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BRCA2 Protein / metabolism
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Cell Line, Tumor
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DNA Repair
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Gene Expression Regulation, Neoplastic
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Gene Silencing
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Humans
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Models, Molecular
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Mutation
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Phthalazines / chemistry
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Phthalazines / pharmacology*
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Piperazines / chemistry
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Piperazines / pharmacology*
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Protein Conformation
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Rad51 Recombinase / antagonists & inhibitors*
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Rad51 Recombinase / metabolism
Substances
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Antineoplastic Agents
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BRCA2 Protein
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BRCA2 protein, human
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Phthalazines
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Piperazines
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RAD51 protein, human
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Rad51 Recombinase
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olaparib