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CHK1 inhibition exacerbates replication stress induced by IGF blockade

We recently reported that genetic or pharmacological inhibition of insulin-like growth factor receptor (IGF-1R) slows DNA replication and induces replication stress by downregulating the regulatory subunit RRM2 of ribonucleotide reductase, perturbing deoxynucleotide triphosphate (dNTP) supply. Aimin...

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Autores principales: Wu, Xiaoning, Seraia, Elena, Hatch, Stephanie B., Wan, Xiao, Ebner, Daniel V., Aroldi, Francesca, Jiang, Yanyan, Ryan, Anderson J., Bogenrieder, Thomas, Weyer-Czernilofsky, Ulrike, Rieunier, Guillaume, Macaulay, Valentine M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8782724/
https://www.ncbi.nlm.nih.gov/pubmed/34773074
http://dx.doi.org/10.1038/s41388-021-02080-1
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author Wu, Xiaoning
Seraia, Elena
Hatch, Stephanie B.
Wan, Xiao
Ebner, Daniel V.
Aroldi, Francesca
Jiang, Yanyan
Ryan, Anderson J.
Bogenrieder, Thomas
Weyer-Czernilofsky, Ulrike
Rieunier, Guillaume
Macaulay, Valentine M.
author_facet Wu, Xiaoning
Seraia, Elena
Hatch, Stephanie B.
Wan, Xiao
Ebner, Daniel V.
Aroldi, Francesca
Jiang, Yanyan
Ryan, Anderson J.
Bogenrieder, Thomas
Weyer-Czernilofsky, Ulrike
Rieunier, Guillaume
Macaulay, Valentine M.
author_sort Wu, Xiaoning
collection PubMed
description We recently reported that genetic or pharmacological inhibition of insulin-like growth factor receptor (IGF-1R) slows DNA replication and induces replication stress by downregulating the regulatory subunit RRM2 of ribonucleotide reductase, perturbing deoxynucleotide triphosphate (dNTP) supply. Aiming to exploit this effect in therapy we performed a compound screen in five breast cancer cell lines with IGF neutralising antibody xentuzumab. Inhibitor of checkpoint kinase CHK1 was identified as a top screen hit. Co-inhibition of IGF and CHK1 caused synergistic suppression of cell viability, cell survival and tumour growth in 2D cell culture, 3D spheroid cultures and in vivo. Investigating the mechanism of synthetic lethality, we reveal that CHK1 inhibition in IGF-1R depleted or inhibited cells further downregulated RRM2, reduced dNTP supply and profoundly delayed replication fork progression. These effects resulted in significant accumulation of unreplicated single-stranded DNA and increased cell death, indicative of replication catastrophe. Similar phenotypes were induced by IGF:WEE1 co-inhibition, also via exacerbation of RRM2 downregulation. Exogenous RRM2 expression rescued hallmarks of replication stress induced by co-inhibiting IGF with CHK1 or WEE1, identifying RRM2 as a critical target of the functional IGF:CHK1 and IGF:WEE1 interactions. These data identify novel therapeutic vulnerabilities and may inform future trials of IGF inhibitory drugs.
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spelling pubmed-87827242022-01-28 CHK1 inhibition exacerbates replication stress induced by IGF blockade Wu, Xiaoning Seraia, Elena Hatch, Stephanie B. Wan, Xiao Ebner, Daniel V. Aroldi, Francesca Jiang, Yanyan Ryan, Anderson J. Bogenrieder, Thomas Weyer-Czernilofsky, Ulrike Rieunier, Guillaume Macaulay, Valentine M. Oncogene Article We recently reported that genetic or pharmacological inhibition of insulin-like growth factor receptor (IGF-1R) slows DNA replication and induces replication stress by downregulating the regulatory subunit RRM2 of ribonucleotide reductase, perturbing deoxynucleotide triphosphate (dNTP) supply. Aiming to exploit this effect in therapy we performed a compound screen in five breast cancer cell lines with IGF neutralising antibody xentuzumab. Inhibitor of checkpoint kinase CHK1 was identified as a top screen hit. Co-inhibition of IGF and CHK1 caused synergistic suppression of cell viability, cell survival and tumour growth in 2D cell culture, 3D spheroid cultures and in vivo. Investigating the mechanism of synthetic lethality, we reveal that CHK1 inhibition in IGF-1R depleted or inhibited cells further downregulated RRM2, reduced dNTP supply and profoundly delayed replication fork progression. These effects resulted in significant accumulation of unreplicated single-stranded DNA and increased cell death, indicative of replication catastrophe. Similar phenotypes were induced by IGF:WEE1 co-inhibition, also via exacerbation of RRM2 downregulation. Exogenous RRM2 expression rescued hallmarks of replication stress induced by co-inhibiting IGF with CHK1 or WEE1, identifying RRM2 as a critical target of the functional IGF:CHK1 and IGF:WEE1 interactions. These data identify novel therapeutic vulnerabilities and may inform future trials of IGF inhibitory drugs. Nature Publishing Group UK 2021-11-12 2022 /pmc/articles/PMC8782724/ /pubmed/34773074 http://dx.doi.org/10.1038/s41388-021-02080-1 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
Wu, Xiaoning
Seraia, Elena
Hatch, Stephanie B.
Wan, Xiao
Ebner, Daniel V.
Aroldi, Francesca
Jiang, Yanyan
Ryan, Anderson J.
Bogenrieder, Thomas
Weyer-Czernilofsky, Ulrike
Rieunier, Guillaume
Macaulay, Valentine M.
CHK1 inhibition exacerbates replication stress induced by IGF blockade
title CHK1 inhibition exacerbates replication stress induced by IGF blockade
title_full CHK1 inhibition exacerbates replication stress induced by IGF blockade
title_fullStr CHK1 inhibition exacerbates replication stress induced by IGF blockade
title_full_unstemmed CHK1 inhibition exacerbates replication stress induced by IGF blockade
title_short CHK1 inhibition exacerbates replication stress induced by IGF blockade
title_sort chk1 inhibition exacerbates replication stress induced by igf blockade
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8782724/
https://www.ncbi.nlm.nih.gov/pubmed/34773074
http://dx.doi.org/10.1038/s41388-021-02080-1
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