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PARP inhibitor resistance: the underlying mechanisms and clinical implications

Due to the DNA repair defect, BRCA1/2 deficient tumor cells are more sensitive to PARP inhibitors (PARPi) through the mechanism of synthetic lethality. At present, several PAPRi targeting poly (ADP-ribose) polymerase (PARP) have been approved for ovarian cancer and breast cancer indications. However...

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Autores principales: Li, He, Liu, Zhao-Yi, Wu, Nayiyuan, Chen, Yong-Chang, Cheng, Quan, Wang, Jing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305609/
https://www.ncbi.nlm.nih.gov/pubmed/32563252
http://dx.doi.org/10.1186/s12943-020-01227-0
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author Li, He
Liu, Zhao-Yi
Wu, Nayiyuan
Chen, Yong-Chang
Cheng, Quan
Wang, Jing
author_facet Li, He
Liu, Zhao-Yi
Wu, Nayiyuan
Chen, Yong-Chang
Cheng, Quan
Wang, Jing
author_sort Li, He
collection PubMed
description Due to the DNA repair defect, BRCA1/2 deficient tumor cells are more sensitive to PARP inhibitors (PARPi) through the mechanism of synthetic lethality. At present, several PAPRi targeting poly (ADP-ribose) polymerase (PARP) have been approved for ovarian cancer and breast cancer indications. However, PARPi resistance is ubiquitous in clinic. More than 40% BRCA1/2-deficient patients fail to respond to PARPi. In addition, lots of patients acquire PARPi resistance with prolonged oral administration of PARPi. Homologous recombination repair deficient (HRD), as an essential prerequisite of synthetic lethality, plays a vital role in killing tumor cells. Therefore, Homologous recombination repair restoration (HRR) becomes the predominant reason of PARPi resistance. Recently, it was reported that DNA replication fork protection also contributed to PARPi resistance in BRCA1/2-deficient cells and patients. Moreover, various factors, such as reversion mutations, epigenetic modification, restoration of ADP-ribosylation (PARylation) and pharmacological alteration lead to PARPi resistance as well. In this review, we reviewed the underlying mechanisms of PARP inhibitor resistance in detail and summarized the potential strategies to overcome PARPi resistance and increase PARPi sensitivity.
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spelling pubmed-73056092020-06-22 PARP inhibitor resistance: the underlying mechanisms and clinical implications Li, He Liu, Zhao-Yi Wu, Nayiyuan Chen, Yong-Chang Cheng, Quan Wang, Jing Mol Cancer Review Due to the DNA repair defect, BRCA1/2 deficient tumor cells are more sensitive to PARP inhibitors (PARPi) through the mechanism of synthetic lethality. At present, several PAPRi targeting poly (ADP-ribose) polymerase (PARP) have been approved for ovarian cancer and breast cancer indications. However, PARPi resistance is ubiquitous in clinic. More than 40% BRCA1/2-deficient patients fail to respond to PARPi. In addition, lots of patients acquire PARPi resistance with prolonged oral administration of PARPi. Homologous recombination repair deficient (HRD), as an essential prerequisite of synthetic lethality, plays a vital role in killing tumor cells. Therefore, Homologous recombination repair restoration (HRR) becomes the predominant reason of PARPi resistance. Recently, it was reported that DNA replication fork protection also contributed to PARPi resistance in BRCA1/2-deficient cells and patients. Moreover, various factors, such as reversion mutations, epigenetic modification, restoration of ADP-ribosylation (PARylation) and pharmacological alteration lead to PARPi resistance as well. In this review, we reviewed the underlying mechanisms of PARP inhibitor resistance in detail and summarized the potential strategies to overcome PARPi resistance and increase PARPi sensitivity. BioMed Central 2020-06-20 /pmc/articles/PMC7305609/ /pubmed/32563252 http://dx.doi.org/10.1186/s12943-020-01227-0 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data.
spellingShingle Review
Li, He
Liu, Zhao-Yi
Wu, Nayiyuan
Chen, Yong-Chang
Cheng, Quan
Wang, Jing
PARP inhibitor resistance: the underlying mechanisms and clinical implications
title PARP inhibitor resistance: the underlying mechanisms and clinical implications
title_full PARP inhibitor resistance: the underlying mechanisms and clinical implications
title_fullStr PARP inhibitor resistance: the underlying mechanisms and clinical implications
title_full_unstemmed PARP inhibitor resistance: the underlying mechanisms and clinical implications
title_short PARP inhibitor resistance: the underlying mechanisms and clinical implications
title_sort parp inhibitor resistance: the underlying mechanisms and clinical implications
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305609/
https://www.ncbi.nlm.nih.gov/pubmed/32563252
http://dx.doi.org/10.1186/s12943-020-01227-0
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