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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Shrnutí: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.
Bibliografie:ObjectType-Article-1
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ISSN:1474-1776
1474-1784
1474-1784
DOI:10.1038/s41573-022-00558-5