Abstract
Poly(ADP-ribose) polymerases(PARP) synthesize the ADP-ribose polymers onto proteins and play a role in DNA repair. PARP inhibitors block the repair of single-strand breaks, which in turn gives rise to double-strand breaks during DNA replication. Thus, PARP inhibitors elicit synthetic lethality in cancer with BRCA1/2 loss-of-function mutations that hamper homologous recombination repair of double-strand breaks. Olaparib, the first-in-class PARP inhibitor, was approved for treatment of BRCA-mutated ovarian cancer in Europe and the United States in 2014. Other PARP inhibitors under clinical trials include rucaparib, niraparib, veliparib, and the "PARP-trapping" BMN-673. BRCA1/2 sequencing is an FDA-approved companion diagnostics, which predicts the cancer vulnerability to PARP inhibition. Together, synthetic lethal PARP inhibition is a novel promising strategy for cancer intervention even in cases without prominent driver oncogenes.
MeSH terms
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use*
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BRCA1 Protein / genetics
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BRCA2 Protein / genetics
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Benzimidazoles
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DNA Breaks, Double-Stranded / drug effects
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DNA Replication
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DNA, Single-Stranded
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / therapeutic use*
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Humans
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Indazoles
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Indoles
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Molecular Targeted Therapy*
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Mutation
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Neoplasms / drug therapy*
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Neoplasms / genetics*
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Phthalazines / pharmacology
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Phthalazines / therapeutic use*
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Piperazines / pharmacology
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Piperazines / therapeutic use*
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Piperidines
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Poly(ADP-ribose) Polymerase Inhibitors*
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Poly(ADP-ribose) Polymerases / physiology*
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Recombinational DNA Repair / genetics
Substances
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Antineoplastic Agents
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BRCA1 Protein
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BRCA1 protein, human
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BRCA2 Protein
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BRCA2 protein, human
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Benzimidazoles
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DNA, Single-Stranded
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Enzyme Inhibitors
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Indazoles
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Indoles
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Phthalazines
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Piperazines
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Piperidines
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Poly(ADP-ribose) Polymerase Inhibitors
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veliparib
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rucaparib
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talazoparib
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Poly(ADP-ribose) Polymerases
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niraparib
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olaparib