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Emerging strategies for cancer therapy by ATR inhibitors

DNA replication stress (RS) causes genomic instability and vulnerability in cancer cells. To counteract RS, cells have evolved various mechanisms involving the ATR kinase signaling pathway, which regulates origin firing, cell cycle checkpoints, and fork stabilization to secure the fidelity of replic...

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Detalles Bibliográficos
Autores principales: Yano, Kimiyoshi, Shiotani, Bunsyo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10323102/
https://www.ncbi.nlm.nih.gov/pubmed/37189251
http://dx.doi.org/10.1111/cas.15845
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author Yano, Kimiyoshi
Shiotani, Bunsyo
author_facet Yano, Kimiyoshi
Shiotani, Bunsyo
author_sort Yano, Kimiyoshi
collection PubMed
description DNA replication stress (RS) causes genomic instability and vulnerability in cancer cells. To counteract RS, cells have evolved various mechanisms involving the ATR kinase signaling pathway, which regulates origin firing, cell cycle checkpoints, and fork stabilization to secure the fidelity of replication. However, ATR signaling also alleviates RS to support cell survival by driving RS tolerance, thereby contributing to therapeutic resistance. Cancer cells harboring genetic mutations and other changes that disrupt normal DNA replication increase the risk of DNA damage and the levels of RS, conferring addiction to ATR activity for sustainable replication and susceptibility to therapeutic approaches using ATR inhibitors (ATRis). Therefore, clinical trials are currently being conducted to evaluate the efficacy of ATRis as monotherapies or in combination with other drugs and biomarkers. In this review, we discuss recent advances in the elucidation of the mechanisms by which ATR functions in the RS response and its therapeutic relevance when utilizing ATRis.
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spelling pubmed-103231022023-07-07 Emerging strategies for cancer therapy by ATR inhibitors Yano, Kimiyoshi Shiotani, Bunsyo Cancer Sci Review Articles DNA replication stress (RS) causes genomic instability and vulnerability in cancer cells. To counteract RS, cells have evolved various mechanisms involving the ATR kinase signaling pathway, which regulates origin firing, cell cycle checkpoints, and fork stabilization to secure the fidelity of replication. However, ATR signaling also alleviates RS to support cell survival by driving RS tolerance, thereby contributing to therapeutic resistance. Cancer cells harboring genetic mutations and other changes that disrupt normal DNA replication increase the risk of DNA damage and the levels of RS, conferring addiction to ATR activity for sustainable replication and susceptibility to therapeutic approaches using ATR inhibitors (ATRis). Therefore, clinical trials are currently being conducted to evaluate the efficacy of ATRis as monotherapies or in combination with other drugs and biomarkers. In this review, we discuss recent advances in the elucidation of the mechanisms by which ATR functions in the RS response and its therapeutic relevance when utilizing ATRis. John Wiley and Sons Inc. 2023-05-15 /pmc/articles/PMC10323102/ /pubmed/37189251 http://dx.doi.org/10.1111/cas.15845 Text en © 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Review Articles
Yano, Kimiyoshi
Shiotani, Bunsyo
Emerging strategies for cancer therapy by ATR inhibitors
title Emerging strategies for cancer therapy by ATR inhibitors
title_full Emerging strategies for cancer therapy by ATR inhibitors
title_fullStr Emerging strategies for cancer therapy by ATR inhibitors
title_full_unstemmed Emerging strategies for cancer therapy by ATR inhibitors
title_short Emerging strategies for cancer therapy by ATR inhibitors
title_sort emerging strategies for cancer therapy by atr inhibitors
topic Review Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10323102/
https://www.ncbi.nlm.nih.gov/pubmed/37189251
http://dx.doi.org/10.1111/cas.15845
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