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Parp Inhibition and Beyond in Brca- Associated Breast Cancer in Women: A State- Of- The- Art Summary of (Pre) - Clinical Research into Risk Reduction and Clinical Benefits

In mammalian cells, DNA damage response initiates repair by error-free homologous recombination (HRR) or by error-prone non-homogeneous end joining (NHEJ). DNA damage is detected by PARP proteins that facilitate this repair, both in normal cells and in cancer cells. Cells that contain BRCA1/2 mutations have an HRR deficient repair mechanism which may result in unrepaired one-ended double-strand breaks and stalled replication forks, considered as the most lethal cell damage. Here we review the state of the art of the role of Poly (ADP-ribose) polymerase (PARP) inhibitors as a precision targeted anticancer drug in BRCA1/2 mutated female breast cancer. The main role of the archetype PARP1 in the cell nucleus is to detect and adhere to single-strand breaks. This mediates the damage repair, after which cells-including cancer cells-may continue replication. This process is called synthetic lethality. As for PARP monotherapy, progression free survival has been observed using the FDA and EMA approved drugs olaparib and talazoparib. In the case of combined drug therapy, a synergy between veliparib and platinum drugs has been demonstrated. Information regarding adverse effects is limited, but consistently, hematological effects have been described. However, there is need for multicenter trials, preferably conducted without commercial guidance and funding. Some of the available trial results mention resistance to PARP inhibitors. In this review we also describe the various causes of PARP inhibitor resistance as well as the research that indicates how to overcome this phenomenon.

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S1004 Veliparib (ABT-888) Veliparib (ABT-888, NSC 737664) is a potent inhibitor of PARP1 and PARP2 with Ki of 5.2 nM and 2.9 nM in cell-free assays, respectively. It is inactive to SIRT2. Veliparib increases autophagy and apoptosis. Phase 3.

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Autophagy PARP Apoptosis related