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Advances and perspectives of PARP inhibitors

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 lead...

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Autores principales: Yi, Ming, Dong, Bing, Qin, Shuang, Chu, Qian, Wu, Kongming, Luo, Suxia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849303/
https://www.ncbi.nlm.nih.gov/pubmed/31737426
http://dx.doi.org/10.1186/s40164-019-0154-9
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author Yi, Ming
Dong, Bing
Qin, Shuang
Chu, Qian
Wu, Kongming
Luo, Suxia
author_facet Yi, Ming
Dong, Bing
Qin, Shuang
Chu, Qian
Wu, Kongming
Luo, Suxia
author_sort Yi, Ming
collection PubMed
description 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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spelling pubmed-68493032019-11-15 Advances and perspectives of PARP inhibitors Yi, Ming Dong, Bing Qin, Shuang Chu, Qian Wu, Kongming Luo, Suxia Exp Hematol Oncol Review 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. BioMed Central 2019-11-11 /pmc/articles/PMC6849303/ /pubmed/31737426 http://dx.doi.org/10.1186/s40164-019-0154-9 Text en © The Author(s) 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Review
Yi, Ming
Dong, Bing
Qin, Shuang
Chu, Qian
Wu, Kongming
Luo, Suxia
Advances and perspectives of PARP inhibitors
title Advances and perspectives of PARP inhibitors
title_full Advances and perspectives of PARP inhibitors
title_fullStr Advances and perspectives of PARP inhibitors
title_full_unstemmed Advances and perspectives of PARP inhibitors
title_short Advances and perspectives of PARP inhibitors
title_sort advances and perspectives of parp inhibitors
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849303/
https://www.ncbi.nlm.nih.gov/pubmed/31737426
http://dx.doi.org/10.1186/s40164-019-0154-9
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