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Advances and perspectives of PARP inhibitors
Open accessAbstract
DNA damage repair deficiency leads to the increased risk of genome instability and oncogenic transformation. In the meanwhile, this deficiency could be exploited for cancer treatment by inducing excessive genome instability and catastrophic DNA damage. Continuous DNA replication in cancer cells leads to higher demand of DNA repair components. Due to the oncogenic loss of some DNA repair effectors (e.g. BRCA) and incomplete DNA repair repertoire, some cancer cells are addicted to certain DNA repair pathways such as Poly (ADP-ribose) polymerase (PARP)-related single-strand break repair pathway. The interaction between BRCA and PARP is a form of synthetic lethal effect which means the simultaneously functional loss of two genes lead to cell death, while defect in any single gene has a slight effect on cell viability. Based on synthetic lethal theory, Poly (ADP-ribose) polymerase inhibitor (PARPi) was developed aiming to selectively target cancer cells harboring BRCA1/2 mutations. Recently, a growing body of evidence indicated that a broader population of patients could benefit from PARPi therapy far beyond those with germline BRCA1/2 mutated tumors. Numerous biomarkers including homologous recombination deficiency and high level of replication pressure also herald high sensitivity to PARPi treatment. Besides, a series of studies indicated that PARPi-involved combination therapy such as PARPi with additional chemotherapy therapy, immune checkpoint inhibitor, as well as targeted agent had a great advantage in overcoming PARPi resistance and enhancing PARPi efficacy. In this review, we summarized the advances of PARPi in clinical application. Besides, we highlighted multiple promising PARPi-based combination strategies in preclinical and clinical studies.
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![Fig. 1 PARP and PARPis. a The structure schematic of PARP molecule. There are six main domains of PARP1 which include three zinc finger-related domains (DNA binding domains), one BRCA1 C-terminus domain (auto-modification domain), one tryptophan-/glycine-/arginine-rich domain (WGR domain), and one catalytic domain. The catalytic domain of PARP1 consists of two subdomains: one helical domain (HD) and one ADP-ribosyltransferase catalytic domain (ART). b Three-dimensional structure of PARP1 molecule. The above structures were presented by PyMOL Molecular Graphics System (PDB ID: 5XST [104]). c The chemistry structural formula of PARPis. d The function of PARP and synthetic lethal interaction between PARP and HR. Once DNA SSB emerges, PARP1 could recognizes and interacts with SSB by its zinc finger-related domains. After PARP1 binding to damaged DNA chains, the auto-inhibitory function of HD is abrogated and the catalytic function of ART is activated. This catalytic activity leads to the generation of PAR chains on a series of target proteins which promotes the recruitment of DNA repair effectors and chromatin remodeling. Then the auto-PARylation on PARP1 protein causes the dissociation of PARP1 from DNA chains and restores the auto-inhibitory status of PARP1. For HR deficient tumor cells, active SSB repair pathways is the vital prerequisites for cell survival. After PARPi treatment, NHEJ is used to repair PARPi-introduced DSB. However, NHEJ is a rapid as well as error-prone repair pathway by direct ligation. Due to the low-fidelity, NHEJ often produces plenty of chromosomal rearrangements and these unsustainable DNA damages are harmful to cell viability](/paper-figures/b8cba8b0fd6c416cb14979296998b864/advances-and-perspectives-of-parp-inhibitors-figure-1.jpg)
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“As the core of SSB repair, PARP is the ideal target for drug development [222].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [222]
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Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy
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Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers
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Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation
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PARP inhibitors: Synthetic lethality in the clinic
Lord, C. J., & Ashworth, A. (2017) · Science · doi:10.1126/science.aam7344 · Cited by 3,013
Selective Inhibition of Tumor Oncogenes by Disruption of Super-Enhancers
Lovén, J., Hoke, H. A., Lin, C. Y., Lau, A., Orlando, D. A., Vakoc, C. R., Bradner, J. E., Lee, T. I., & Young, R. A. (2013) · Cell · doi:10.1016/j.cell.2013.03.036 · Cited by 2,961
Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer
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Comprehensive genomic profiles of small cell lung cancer
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Maintenance Olaparib for Germline BRCA -Mutated Metastatic Pancreatic Cancer
Golan, T., Hammel, P., Reni, M., Van Cutsem, E., Macarulla, T., Hall, M. J., Park, J.-O., Hochhauser, D., Arnold, D., Oh, D.-Y., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1903387 · Cited by 2,302
Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors
Murai, J., Huang, S.-Y. N., Das, B. B., Renaud, A., Zhang, Y., Doroshow, J. H., Ji, J. J., Takeda, S., & Pommier, Y. G. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-2753 · Cited by 2,276
Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation
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Metadata
- Authors
- Yi, M., Dong, B., Qin, S., Chu, Q., Wu, K., & Luo, S.
- Affiliations
- Tongji Hospital (CN)
- Zhengzhou University (CN)
- Corresponding author
- Wu, Kongming
- Luo, Suxia
- Venue
- Experimental Hematology & Oncology
- Published
- 2019-11-11
- Volume
- 8
- Issue
- 1
- Pages
- 29-29
- ISSN
- 2162-3619 (ISSN-L)
- PMC
- PMC6849303
- OpenAlex
- W2987653633
- Cited by
- 117
- References
- 104
- Citations by year
- 2026: 4 · 2025: 14 · 2024: 7 · 2023: 18 · 2022: 19 · 2021: 33 · 2020: 22
- FWCI
- 1.76
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Experimental Hematology and Oncology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Natural Science Foundation of China (81874120, 81572608, 81672984)
- Wuhan Municipal Science and Technology Bureau (2017060201010170)
- Natural Science Foundation of Henan Province (162300410266)
- Topics
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Keywords
- PARP inhibitors, DNA repair deficiency, synthetic lethality, BRCA mutations, homologous recombination deficiency, single-strand break repair, genomic instability, PARP inhibitor resistance, combination therapy, immune checkpoint inhibitors, combination chemotherapy
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