PARP

Official Full Name

Poly (ADP-ribose) polymerase

Background

Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in a number of cellular processes involving mainly DNA repair and programmed cell death.

Synonyms

Poly (ADP-ribose) polymerase; PARP;

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Detailed Information

PARP inhibition works as a therapeutic option in Melanoma treatment

PARP inhibition and immunotherapy were used in the treatment of melanomas, which have homologous recombination DNA damage repair pathways. In the treatment of cancers with BRCA mutation, PARP inhibition has been established to be therapy through synthetic lethality. More than this, in the treatment of other types of homologous recombination defects, it has also been found to have some applications. In 20%-40% of cutaneous melanoma, PARP gene was found to be mutated. Despite the transformation brought out by the immunotherapy used in the treatment of melanoma to get improvements in patient outcomes, the issue of resistance and tumor escape of this monotherapy remains to be unresolved. So, new therapies, combination strategies and biomarker-guided decision making are desired to be made to benefit from treatment. For example, the application of PARP inhibition has been extended to the treatment of melanoma, which is classified into the BRCA-negative cancers with high rate of DNA damage repair pathway mutations. The therapeutic effect of PARP inhibition in combination with immunotherapy can be augmented through multi-faceted immune-priming capabilities.

Future perspectives of PARP applications

The combination of PARP and immune checkpoint inhibitor therapy was demonstrated to be with a synergistic effect in the cell line and preclinical experiments, double-strand DNA breaks induced by the PARP inhibition through the cGAS-STING pathway can give rise to genomic instability, which can increase tumor burden and induce immunogenicity. Inflammation, immune priming and upregulation of PD-1 expression can be also promoted by the DNA unrepairing. Those mentioned associations between PARP and the tumor-immune response may indicate that immune checkpoint inhibition can be sensitized by PARP inhibition. There is also an ongoing phase II clinical trial investigating the combination therapy, whose efficacy and safety are needed to determine, for the HR-DDR mutated patients may benefit a lot from it.

Figure 1. The mechanism of the action of PARP inhibitors. (Feiyue Zheng, et al. 2020)

References:

Zheng F, Zhang Y, Chen S, et al. Mechanism and current progress of Poly ADP-ribose polymerase (PARP) inhibitors in the treatment of ovarian cancer. Biomedicine & Pharmacotherapy, 2020, 123: 109661.
Chan W Y, Brown L J, Reid L, et al. PARP Inhibitors in Melanoma—An Expanding Therapeutic Option?. Cancers, 2021, 13(18): 4520.

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