Poly(ADP-ribose) polymerase inhibition: a new direction for BRCAand triple-negative breast cancer?

Abstract

Inhibitors of poly(ADP-ribose) polymerase (PARP)-mediated DNA repair have shown promise in early clinical studies in the treatment of specific subgroups of breast cancer. Notably, phase II trials indicate that olaparib, an oral PARP inhibitor, has activity as a single agent in BRCA-related tumours, and that a combination of iniparib, an intravenous PARP inhibitor, and chemotherapy offers a survival advantage, compared with chemotherapy alone, in triple-negative breast cancer. Phase III data on the latter indication are expected in 2011. Intriguingly, iniparib does not increase toxicity when used as a chemo-potentiating agent, suggesting that it differs in its mechanism of action from other agents in this class. Overall, PARP inhibitors represent a potentially important new class of anti-cancer agents with two potential modes of action, as single agents causing synthetic lethality and as chemo-potentiating agents.

Genetic and Genomic Factors in Breast Cancer

“…Cell survival assays show that cell lines lacking wildtype BRCA1 or BRCA2 were extremely sensitive to PARP inhibitors compared to heterozygous mutant or the wildtype cells [ 60 ] . These results suggest the potential use of PARP inhibitors in the treatment of BRCA1 -and BRCA2 -related breast and ovarian cancers with recent and ongoing clinical trials showing promising results and clinical outcomes [ 61 ] .…”

PI3K-AKT-mTOR Pathway Cooperates with the DNA Damage Repair Pathway: Carcinogenesis in Triple-Negative Breast Cancers and Beyond

“…One of the most agreeable conclusions amidst of different controversies regarding the usefulness of PARP inhibitor(s) is the possibility that PARP inhibitors can target the BRCA-ness in order to inhibit DDR which in turn induces apoptosis [7,17,35,72,85,128,133,147]. The premise of the use of PARP inhibitors in BRCA1/2-associated and sporadic cancers have come a long way based on the concept of "synthetic lethality" [16,46,53,55].…”

The Tyrosine Kinase Inhibitor E-3810 Combined with Paclitaxel Inhibits the Growth of Advanced-Stage Triple-Negative Breast Cancer Xenografts

“…Therefore, it is not amenable to hormone therapy or the anti-HER2 monoclonal antibody trastuzumab, and systemic treatment options are currently limited to cytotoxic therapy, including paclitaxel. A number of target approaches are under clinical evaluation: PARP inhibitors, antiangiogenic drugs, and anti-EGFR agents (11,12). FGFR signaling may be important for the growth of a certain proportion of TNBC, providing a rationale for assessing FGFR inhibitors, or therapies targeting FGF2 ligand in TNBC and basal-like breast cancer (13).…”