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The cytosolic iron–sulfur cluster assembly (CIA) pathway is required for replication stress tolerance of cancer cells to Chk1 and ATR inhibitors

The relationship between ATR/Chk1 activity and replication stress, coupled with the development of potent and tolerable inhibitors of this pathway, has led to the clinical exploration of ATR and Chk1 inhibitors (ATRi/Chk1i) as anticancer therapies for single-agent or combinatorial application. The c...

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Autores principales: Redwood, Abena B., Zhang, Xiaomei, Seth, Sahil B., Ge, Zhongqi, Bindeman, Wendy E., Zhou, Xinhui, Sinha, Vidya C., Heffernan, Timothy P., Piwnica-Worms, Helen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8639742/
https://www.ncbi.nlm.nih.gov/pubmed/34857765
http://dx.doi.org/10.1038/s41523-021-00353-2
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author Redwood, Abena B.
Zhang, Xiaomei
Seth, Sahil B.
Ge, Zhongqi
Bindeman, Wendy E.
Zhou, Xinhui
Sinha, Vidya C.
Heffernan, Timothy P.
Piwnica-Worms, Helen
author_facet Redwood, Abena B.
Zhang, Xiaomei
Seth, Sahil B.
Ge, Zhongqi
Bindeman, Wendy E.
Zhou, Xinhui
Sinha, Vidya C.
Heffernan, Timothy P.
Piwnica-Worms, Helen
author_sort Redwood, Abena B.
collection PubMed
description The relationship between ATR/Chk1 activity and replication stress, coupled with the development of potent and tolerable inhibitors of this pathway, has led to the clinical exploration of ATR and Chk1 inhibitors (ATRi/Chk1i) as anticancer therapies for single-agent or combinatorial application. The clinical efficacy of these therapies relies on the ability to ascertain which patient populations are most likely to benefit, so there is intense interest in identifying predictive biomarkers of response. To comprehensively evaluate the components that modulate cancer cell sensitivity to replication stress induced by Chk1i, we performed a synthetic-lethal drop-out screen in a cell line derived from a patient with triple-negative breast cancer (TNBC), using a pooled barcoded shRNA library targeting ~350 genes involved in DNA replication, DNA damage repair, and cycle progression. In addition, we sought to compare the relative requirement of these genes when DNA fidelity is challenged by clinically relevant anticancer breast cancer drugs, including cisplatin and PARP1/2 inhibitors, that have different mechanisms of action. This global comparison is critical for understanding not only which agents should be used together for combinatorial therapies in breast cancer patients, but also the genetic context in which these therapies will be most effective, and when a single-agent therapy will be sufficient to provide maximum therapeutic benefit to the patient. We identified unique potentiators of response to ATRi/Chk1i and describe a new role for components of the cytosolic iron–sulfur assembly (CIA) pathway, MMS19 and CIA2B-FAM96B, in replication stress tolerance of TNBC.
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spelling pubmed-86397422021-12-15 The cytosolic iron–sulfur cluster assembly (CIA) pathway is required for replication stress tolerance of cancer cells to Chk1 and ATR inhibitors Redwood, Abena B. Zhang, Xiaomei Seth, Sahil B. Ge, Zhongqi Bindeman, Wendy E. Zhou, Xinhui Sinha, Vidya C. Heffernan, Timothy P. Piwnica-Worms, Helen NPJ Breast Cancer Article The relationship between ATR/Chk1 activity and replication stress, coupled with the development of potent and tolerable inhibitors of this pathway, has led to the clinical exploration of ATR and Chk1 inhibitors (ATRi/Chk1i) as anticancer therapies for single-agent or combinatorial application. The clinical efficacy of these therapies relies on the ability to ascertain which patient populations are most likely to benefit, so there is intense interest in identifying predictive biomarkers of response. To comprehensively evaluate the components that modulate cancer cell sensitivity to replication stress induced by Chk1i, we performed a synthetic-lethal drop-out screen in a cell line derived from a patient with triple-negative breast cancer (TNBC), using a pooled barcoded shRNA library targeting ~350 genes involved in DNA replication, DNA damage repair, and cycle progression. In addition, we sought to compare the relative requirement of these genes when DNA fidelity is challenged by clinically relevant anticancer breast cancer drugs, including cisplatin and PARP1/2 inhibitors, that have different mechanisms of action. This global comparison is critical for understanding not only which agents should be used together for combinatorial therapies in breast cancer patients, but also the genetic context in which these therapies will be most effective, and when a single-agent therapy will be sufficient to provide maximum therapeutic benefit to the patient. We identified unique potentiators of response to ATRi/Chk1i and describe a new role for components of the cytosolic iron–sulfur assembly (CIA) pathway, MMS19 and CIA2B-FAM96B, in replication stress tolerance of TNBC. Nature Publishing Group UK 2021-12-02 /pmc/articles/PMC8639742/ /pubmed/34857765 http://dx.doi.org/10.1038/s41523-021-00353-2 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Redwood, Abena B.
Zhang, Xiaomei
Seth, Sahil B.
Ge, Zhongqi
Bindeman, Wendy E.
Zhou, Xinhui
Sinha, Vidya C.
Heffernan, Timothy P.
Piwnica-Worms, Helen
The cytosolic iron–sulfur cluster assembly (CIA) pathway is required for replication stress tolerance of cancer cells to Chk1 and ATR inhibitors
title The cytosolic iron–sulfur cluster assembly (CIA) pathway is required for replication stress tolerance of cancer cells to Chk1 and ATR inhibitors
title_full The cytosolic iron–sulfur cluster assembly (CIA) pathway is required for replication stress tolerance of cancer cells to Chk1 and ATR inhibitors
title_fullStr The cytosolic iron–sulfur cluster assembly (CIA) pathway is required for replication stress tolerance of cancer cells to Chk1 and ATR inhibitors
title_full_unstemmed The cytosolic iron–sulfur cluster assembly (CIA) pathway is required for replication stress tolerance of cancer cells to Chk1 and ATR inhibitors
title_short The cytosolic iron–sulfur cluster assembly (CIA) pathway is required for replication stress tolerance of cancer cells to Chk1 and ATR inhibitors
title_sort cytosolic iron–sulfur cluster assembly (cia) pathway is required for replication stress tolerance of cancer cells to chk1 and atr inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8639742/
https://www.ncbi.nlm.nih.gov/pubmed/34857765
http://dx.doi.org/10.1038/s41523-021-00353-2
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