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Review
. 2019 Mar 30;8(4):435.
doi: 10.3390/jcm8040435.

PARP Inhibitors as a Therapeutic Agent for Homologous Recombination Deficiency in Breast Cancers

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Free PMC article
Review

PARP Inhibitors as a Therapeutic Agent for Homologous Recombination Deficiency in Breast Cancers

Man Yee T Keung et al. J Clin Med. .
Free PMC article

Abstract

Poly (ADP-ribose) polymerases (PARPs) play an important role in various cellular processes, such as replication, recombination, chromatin remodeling, and DNA repair. Emphasizing PARP's role in facilitating DNA repair, the PARP pathway has been a target for cancer researchers in developing compounds which selectively target cancer cells and increase sensitivity of cancer cells to other anticancer agents, but which also leave normal cells unaffected. Since certain tumors (BRCA1/2 mutants) have deficient homologous recombination repair pathways, they depend on PARP-mediated base excision repair for survival. Thus, inhibition of PARP is a promising strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Although PARP inhibitor therapy has predominantly targeted BRCA-mutated cancers, this review also highlights the growing conversation around PARP inhibitor treatment for non-BRCA-mutant tumors, those which exhibit BRCAness and homologous recombination deficiency. We provide an update on the field's progress by considering PARP inhibitor mechanisms, predictive biomarkers, and clinical trials of PARP inhibitors in development. Bringing light to these findings would provide a basis for expanding the use of PARP inhibitors beyond BRCA-mutant breast tumors.

Keywords: BRCA; BRCAness; PARP; PARP inhibitors; biomarkers; breast cancer; resistance.

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
PARP pathway overview. Cellular stress such as oxidative stress from reactive oxygen species causes DNA damage in the form of single- and double-strand breaks. Under normal conditions, the PARP pathway is activated. ADP-ribose units are recruited to sites of DNA strand breaks in a process known as PARylation. With the assistance of PARP and other DNA repair enzymes, repair of DNA strand breaks occurs, and the cell remains viable. This figure provides an overview of what happens in the presence of a PARP inhibitor in BRCA-mutated cells which have defects in the homologous recombination repair pathway. The PARP inhibitor mediates inhibition of PARylation, thereby preventing repair of DNA strand breaks via the PARP pathway or the homologous recombination repair pathway. This synthetic lethality in which both repair pathways are nonfunctional contributes to unrepaired single-strand breaks and double-strand breaks; accumulation of double-strand breaks ultimately leads to apoptosis and cell death. (DSB = double-strand break; PARP = poly (ADP-ribose) polymerase; ROS = reactive oxygen species)
Figure 2
Figure 2
Homologous recombination deficiency (HRD) and genomic alterations. (a) Both germline mutations and somatic mutations involving HR-related genes, including BRCA1 and BRCA2, may be associated with HRD. (b) Promoter methylation involves addition of a methyl group to CpG islands, which ultimately silences gene expression. This is an epigenetic mechanism implicated in HRD. (c) Copy number aberrations/alterations alter chromosomal structure and are a hallmark of HRD. (d) Genomic scars are examined and can be scored to measure the level of HRD phenotype in a sample. (e) Mutational signatures are patterns of base pair mutations that measure levels of DNA damage in a sample. Pictured here is a representation of signature 3, a mutational signature highly prevalent in tumors with BRCAness and also one of a few distinct mutational signatures found in breast cancer. Signature 3, among other mutational signatures, was characterized in 2013 by Alexandrov et al. [42].

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