Targeting replication stress in cancer therapy

Replication stress is a major cause of genomic instability and a crucial vulnerability of cancer cells. This vulnerability can be therapeutically targeted by inhibiting kinases that coordinate the DNA damage response with cell cycle control, including ATR, CHK1, WEE1 and MYT1 checkpoint kinases. In...

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Vydáno v:	Nature reviews. Drug discovery Ročník 22; číslo 1; s. 38 - 58
Hlavní autoři:	da Costa, Alexandre André B A, Chowdhury, Dipanjan, Shapiro, Geoffrey I, D'Andrea, Alan D, Konstantinopoulos, Panagiotis A
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	England Nature Publishing Group 01.01.2023
Témata:	Cancer Cell cycle Cell Cycle Proteins - genetics Cell Cycle Proteins - metabolism Cell Cycle Proteins - therapeutic use Checkpoint Kinase 1 - genetics Checkpoint Kinase 1 - metabolism Checkpoint Kinase 1 - therapeutic use Chemotherapy DNA Damage DNA Replication Humans Immune checkpoint inhibitors Neoplasms - drug therapy Neoplasms - genetics
ISSN:	1474-1776, 1474-1784, 1474-1784
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Abstract	Replication stress is a major cause of genomic instability and a crucial vulnerability of cancer cells. This vulnerability can be therapeutically targeted by inhibiting kinases that coordinate the DNA damage response with cell cycle control, including ATR, CHK1, WEE1 and MYT1 checkpoint kinases. In addition, inhibiting the DNA damage response releases DNA fragments into the cytoplasm, eliciting an innate immune response. Therefore, several ATR, CHK1, WEE1 and MYT1 inhibitors are undergoing clinical evaluation as monotherapies or in combination with chemotherapy, poly[ADP-ribose]polymerase (PARP) inhibitors, or immune checkpoint inhibitors to capitalize on high replication stress, overcome therapeutic resistance and promote effective antitumour immunity. Here, we review current and emerging approaches for targeting replication stress in cancer, from preclinical and biomarker development to clinical trial evaluation.
AbstractList	Replication stress is a major cause of genomic instability and a crucial vulnerability of cancer cells. This vulnerability can be therapeutically targeted by inhibiting kinases that coordinate the DNA damage response with cell cycle control, including ATR, CHK1, WEE1 and MYT1 checkpoint kinases. In addition, inhibiting the DNA damage response releases DNA fragments into the cytoplasm, eliciting an innate immune response. Therefore, several ATR, CHK1, WEE1 and MYT1 inhibitors are undergoing clinical evaluation as monotherapies or in combination with chemotherapy, poly[ADP-ribose]polymerase (PARP) inhibitors, or immune checkpoint inhibitors to capitalize on high replication stress, overcome therapeutic resistance and promote effective antitumour immunity. Here, we review current and emerging approaches for targeting replication stress in cancer, from preclinical and biomarker development to clinical trial evaluation.Replication stress is a major cause of genomic instability and a crucial vulnerability of cancer cells. This vulnerability can be therapeutically targeted by inhibiting kinases that coordinate the DNA damage response with cell cycle control, including ATR, CHK1, WEE1 and MYT1 checkpoint kinases. In addition, inhibiting the DNA damage response releases DNA fragments into the cytoplasm, eliciting an innate immune response. Therefore, several ATR, CHK1, WEE1 and MYT1 inhibitors are undergoing clinical evaluation as monotherapies or in combination with chemotherapy, poly[ADP-ribose]polymerase (PARP) inhibitors, or immune checkpoint inhibitors to capitalize on high replication stress, overcome therapeutic resistance and promote effective antitumour immunity. Here, we review current and emerging approaches for targeting replication stress in cancer, from preclinical and biomarker development to clinical trial evaluation. Replication stress is a major cause of genomic instability and a crucial vulnerability of cancer cells. This vulnerability can be therapeutically targeted by inhibiting kinases that coordinate the DNA damage response with cell cycle control, including ATR, CHK1, WEE1 and MYT1 checkpoint kinases. In addition, inhibiting the DNA damage response releases DNA fragments into the cytoplasm, eliciting an innate immune response. Therefore, several ATR, CHK1, WEE1 and MYT1 inhibitors are undergoing clinical evaluation as monotherapies or in combination with chemotherapy, poly[ADP-ribose]polymerase (PARP) inhibitors, or immune checkpoint inhibitors to capitalize on high replication stress, overcome therapeutic resistance and promote effective antitumour immunity. Here, we review current and emerging approaches for targeting replication stress in cancer, from preclinical and biomarker development to clinical trial evaluation. Replication stress is a major cause of genomic instability and a crucial vulnerability of cancer cells. This vulnerability can be therapeutically targeted by inhibiting kinases that coordinate the DNA damage response with cell cycle control, including ATR, CHK1, WEE1 and MYT1 checkpoint kinases. In addition, inhibiting the DNA damage response releases DNA fragments into the cytoplasm, eliciting an innate immune response. Therefore, several ATR, CHK1, WEE1 and MYT1 inhibitors are undergoing clinical evaluation as monotherapies or in combination with chemotherapy, poly[ADP-ribose]polymerase (PARP) inhibitors, or immune checkpoint inhibitors to capitalize on high replication stress, overcome therapeutic resistance and promote effective antitumour immunity. Here, we review current and emerging approaches for targeting replication stress in cancer, from preclinical and biomarker development to clinical trial evaluation.Replication stress is a cause of genome instability in cancer cells. This Review discusses strategies to increase replicative stress by inhibiting the checkpoint kinases that coordinate DNA damage response and cell cycle, as well as combination strategies with other targeted therapies.
Author	D'Andrea, Alan D da Costa, Alexandre André B A Chowdhury, Dipanjan Shapiro, Geoffrey I Konstantinopoulos, Panagiotis A
Author_xml	– sequence: 1 givenname: Alexandre André B A orcidid: 0000-0002-1631-0105 surname: da Costa fullname: da Costa, Alexandre André B A organization: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA – sequence: 2 givenname: Dipanjan orcidid: 0000-0001-5645-3752 surname: Chowdhury fullname: Chowdhury, Dipanjan organization: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA – sequence: 3 givenname: Geoffrey I surname: Shapiro fullname: Shapiro, Geoffrey I organization: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA – sequence: 4 givenname: Alan D orcidid: 0000-0001-6168-6294 surname: D'Andrea fullname: D'Andrea, Alan D email: Alan_Dandrea@dfci.harvard.edu, Alan_Dandrea@dfci.harvard.edu organization: Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA, USA. Alan_Dandrea@dfci.harvard.edu – sequence: 5 givenname: Panagiotis A orcidid: 0000-0002-1032-1479 surname: Konstantinopoulos fullname: Konstantinopoulos, Panagiotis A email: Panagiotis_konstantinopoulos@dfci.harvard.edu organization: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Panagiotis_konstantinopoulos@dfci.harvard.edu
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Snippet	Replication stress is a major cause of genomic instability and a crucial vulnerability of cancer cells. This vulnerability can be therapeutically targeted by...
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SubjectTerms	Cancer Cell cycle Cell Cycle Proteins - genetics Cell Cycle Proteins - metabolism Cell Cycle Proteins - therapeutic use Checkpoint Kinase 1 - genetics Checkpoint Kinase 1 - metabolism Checkpoint Kinase 1 - therapeutic use Chemotherapy DNA Damage DNA Replication Humans Immune checkpoint inhibitors Neoplasms - drug therapy Neoplasms - genetics
Title	Targeting replication stress in cancer therapy
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