Effects of PARP inhibitors in BRCA gene-mutated ovarian cancer

Ovarian cancer is a cancerous growth arising from the ovary, and remains the leading cause of death from gynecological cancer, accounting for more than 140,000 deaths per year worldwide. The risk of developing ovarian cancer appears to be affected by several factors, and 10% of ovarian cancer patients have a family history of the disease. Certain genes defects (BRCA1 and BRCA2) are considered to be responsible for a small number of ovarian cancer cases.
Both BRCA genes are tumor suppressor genes producing proteins that have important roles in the repair of DNA double-strand breaks (DSBs) via the homologous recombination (HR) pathway and are therefore critical for the maintenance of genome integrity. BRCA1 and BRCA2 defective cells are therefore particularly sensitive to DNA cross-linking agents, such as mitomycin C, carboplatin, and cisplatin.

PARP is a nuclear enzyme that facilitates the repair of single strand breaks via the base excision repair pathway (BER). Cell lines lacking wild-type BRCA1 or BRCA2 are reported to be more sensitive to potent PARP inhibitors compared to heterozygous mutant or wild-type cells[1]. A synthetic lethal interaction has been demonstrated between BRCA1 or BRCA2 mutations and PARP. PARP inhibitors are, therefore, highly selectively lethal to cells that lack functional BRCA1 or BRCA2, and are associated with minimal toxicity to normal cells[2]. Furthermore, some inhibitors has been used in clinical studies in BRCA mutation–associated ovarian cancer, including the phase 1 trial of the PARP inhibitor olaparib, the phase 2 study of AG-014699, and the phase 2 study of iniparib[3,4].
Taken together, PARP inhibitors may provide a effective strategy to prevent the development of BRCA mutation–related cancers.

[1]. J Clin Oncol. 2008;26 (22):3785–90.
[2]. Nature. 2005;434 (7035):913–7.
[3]. New Engl J Med. 2009;361(2):123–34.
[4]. J Clin Oncol. 2011;29(suppl; abstr 3104).

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Cat.No. Product Name Information
S1060 Olaparib (AZD2281) Olaparib (AZD2281, KU0059436) is a selective inhibitor of PARP1/2 with IC50 of 5 nM/1 nM in cell-free assays, 300-times less effective against tankyrase-1. Olaparib induces significant autophagy that is associated with mitophagy in cells with BRCA mutations.
S1098 Rucaparib (AG-014699) phosphate Rucaparib (AG-014699, PF-01367338) is an inhibitor of PARP with Ki of 1.4 nM for PARP1 in a cell-free assay, also showing binding affinity to eight other PARP domains. Phase 3.
S1087 Iniparib (BSI-201) Iniparib (BSI-201, NSC-746045, IND-71677) is a PARP1 inhibitor with demonstrated effectiveness in triple-negative breast cancer (TNBC). Phase 3.

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