PARP Inhibitors: Clinical Limitations and Recent Attempts to Overcome Them

Dongha Kim; Hye Jin Nam

doi:10.3390/ijms23158412

PARP Inhibitors: Clinical Limitations and Recent Attempts to Overcome Them

Dongha Kim, Hye Jin Nam

Department of Anatomy

Research output: Contribution to journal › Review article › peer-review

53 Scopus citations

Abstract

PARP inhibitors are the first clinically approved drugs that were developed based on synthetic lethality. PARP inhibitors have shown promising outcomes since their clinical applications and have recently been approved as maintenance treatment for cancer patients with BRCA mutations. PARP inhibitors also exhibit positive results even in patients without homologous recombination (HR) deficiency. Therapeutic effects were successfully achieved; however, the development of resistance was unavoidable. Approximately 40–70% of patients are likely to develop resistance. Here, we describe the mechanisms of action of PARP inhibitors, the causes of resistance, and the various efforts to overcome resistance. Particularly, we determined the survival probability of cancer patients according to the expression patterns of genes associated with HR restoration, which are critical for the development of PARP inhibitor resistance. Furthermore, we discuss the innovative attempts to degrade PARP proteins by chemically modifying PARP inhibitors. These efforts would enhance the efficacy of PARP inhibitors or expand the scope of their usage.

Original language	English
Article number	8412
Journal	International Journal of Molecular Sciences
Volume	23
Issue number	15
DOIs	https://doi.org/10.3390/ijms23158412
State	Published - Aug 2022

Bibliographical note

Funding Information:
This work was supported by a grant from the Bio & Medical Technology Development Program of the National Research Foundation (NRF), which is funded by the Ministry of Science and ICT (2020M3A9I4036072) to H.J.N; Basic Research Program of the NRF, which is funded by the Ministry of Science and ICT (2022R1A2C4002022) to D.K.; Basic Research Laboratory Program of the NRF, which is funded by the Ministry of Science and ICT (2021R1A4A3031875) to D.K.; The financial support of the Catholic Medical Center Research Foundation made in the program year of 2021 to D.K.

Publisher Copyright:
© 2022 by the authors.

Keywords

homologous recombination (HR)
hydrophobic tagging
PARP1
PROTAC
resistance to PARP inhibitor
synthetic lethality

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "PARP Inhibitors: Clinical Limitations and Recent Attempts to Overcome Them",

abstract = "PARP inhibitors are the first clinically approved drugs that were developed based on synthetic lethality. PARP inhibitors have shown promising outcomes since their clinical applications and have recently been approved as maintenance treatment for cancer patients with BRCA mutations. PARP inhibitors also exhibit positive results even in patients without homologous recombination (HR) deficiency. Therapeutic effects were successfully achieved; however, the development of resistance was unavoidable. Approximately 40–70% of patients are likely to develop resistance. Here, we describe the mechanisms of action of PARP inhibitors, the causes of resistance, and the various efforts to overcome resistance. Particularly, we determined the survival probability of cancer patients according to the expression patterns of genes associated with HR restoration, which are critical for the development of PARP inhibitor resistance. Furthermore, we discuss the innovative attempts to degrade PARP proteins by chemically modifying PARP inhibitors. These efforts would enhance the efficacy of PARP inhibitors or expand the scope of their usage.",

keywords = "homologous recombination (HR), hydrophobic tagging, PARP1, PROTAC, resistance to PARP inhibitor, synthetic lethality",

author = "Dongha Kim and Nam, {Hye Jin}",

note = "Funding Information: This work was supported by a grant from the Bio & Medical Technology Development Program of the National Research Foundation (NRF), which is funded by the Ministry of Science and ICT (2020M3A9I4036072) to H.J.N; Basic Research Program of the NRF, which is funded by the Ministry of Science and ICT (2022R1A2C4002022) to D.K.; Basic Research Laboratory Program of the NRF, which is funded by the Ministry of Science and ICT (2021R1A4A3031875) to D.K.; The financial support of the Catholic Medical Center Research Foundation made in the program year of 2021 to D.K. Publisher Copyright: {\textcopyright} 2022 by the authors.",

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N1 - Funding Information: This work was supported by a grant from the Bio & Medical Technology Development Program of the National Research Foundation (NRF), which is funded by the Ministry of Science and ICT (2020M3A9I4036072) to H.J.N; Basic Research Program of the NRF, which is funded by the Ministry of Science and ICT (2022R1A2C4002022) to D.K.; Basic Research Laboratory Program of the NRF, which is funded by the Ministry of Science and ICT (2021R1A4A3031875) to D.K.; The financial support of the Catholic Medical Center Research Foundation made in the program year of 2021 to D.K. Publisher Copyright: © 2022 by the authors.

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N2 - PARP inhibitors are the first clinically approved drugs that were developed based on synthetic lethality. PARP inhibitors have shown promising outcomes since their clinical applications and have recently been approved as maintenance treatment for cancer patients with BRCA mutations. PARP inhibitors also exhibit positive results even in patients without homologous recombination (HR) deficiency. Therapeutic effects were successfully achieved; however, the development of resistance was unavoidable. Approximately 40–70% of patients are likely to develop resistance. Here, we describe the mechanisms of action of PARP inhibitors, the causes of resistance, and the various efforts to overcome resistance. Particularly, we determined the survival probability of cancer patients according to the expression patterns of genes associated with HR restoration, which are critical for the development of PARP inhibitor resistance. Furthermore, we discuss the innovative attempts to degrade PARP proteins by chemically modifying PARP inhibitors. These efforts would enhance the efficacy of PARP inhibitors or expand the scope of their usage.

AB - PARP inhibitors are the first clinically approved drugs that were developed based on synthetic lethality. PARP inhibitors have shown promising outcomes since their clinical applications and have recently been approved as maintenance treatment for cancer patients with BRCA mutations. PARP inhibitors also exhibit positive results even in patients without homologous recombination (HR) deficiency. Therapeutic effects were successfully achieved; however, the development of resistance was unavoidable. Approximately 40–70% of patients are likely to develop resistance. Here, we describe the mechanisms of action of PARP inhibitors, the causes of resistance, and the various efforts to overcome resistance. Particularly, we determined the survival probability of cancer patients according to the expression patterns of genes associated with HR restoration, which are critical for the development of PARP inhibitor resistance. Furthermore, we discuss the innovative attempts to degrade PARP proteins by chemically modifying PARP inhibitors. These efforts would enhance the efficacy of PARP inhibitors or expand the scope of their usage.

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PARP Inhibitors: Clinical Limitations and Recent Attempts to Overcome Them

Abstract

Bibliographical note

Keywords

UN SDGs

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