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CDC7 inhibition induces replication stress-mediated aneuploid cells with an inflammatory phenotype sensitizing tumors to immune checkpoint blockade

Serine/threonine kinase, cell division cycle 7 (CDC7) is critical for initiating DNA replication. TAK-931 is a specific CDC7 inhibitor, which is a next-generation replication stress (RS) inducer. This study preclinically investigates TAK-931 antitumor efficacy and immunity regulation. TAK-931 induce...

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Autores principales: Morita, Tomoko Yamamori, Yu, Jie, Kashima, Yukie, Kamata, Ryo, Yamamoto, Gaku, Minamide, Tatsunori, Mashima, Chiaki, Yoshiya, Miyuki, Sakae, Yuta, Yamauchi, Toyohiro, Hakozaki, Yumi, Kageyama, Shun-ichiro, Nakamura, Akito, Lightcap, Eric, Tanaka, Kosuke, Niu, Huifeng, Kannan, Karuppiah, Ohashi, Akihiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10657413/
https://www.ncbi.nlm.nih.gov/pubmed/37980406
http://dx.doi.org/10.1038/s41467-023-43274-3
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author Morita, Tomoko Yamamori
Yu, Jie
Kashima, Yukie
Kamata, Ryo
Yamamoto, Gaku
Minamide, Tatsunori
Mashima, Chiaki
Yoshiya, Miyuki
Sakae, Yuta
Yamauchi, Toyohiro
Hakozaki, Yumi
Kageyama, Shun-ichiro
Nakamura, Akito
Lightcap, Eric
Tanaka, Kosuke
Niu, Huifeng
Kannan, Karuppiah
Ohashi, Akihiro
author_facet Morita, Tomoko Yamamori
Yu, Jie
Kashima, Yukie
Kamata, Ryo
Yamamoto, Gaku
Minamide, Tatsunori
Mashima, Chiaki
Yoshiya, Miyuki
Sakae, Yuta
Yamauchi, Toyohiro
Hakozaki, Yumi
Kageyama, Shun-ichiro
Nakamura, Akito
Lightcap, Eric
Tanaka, Kosuke
Niu, Huifeng
Kannan, Karuppiah
Ohashi, Akihiro
author_sort Morita, Tomoko Yamamori
collection PubMed
description Serine/threonine kinase, cell division cycle 7 (CDC7) is critical for initiating DNA replication. TAK-931 is a specific CDC7 inhibitor, which is a next-generation replication stress (RS) inducer. This study preclinically investigates TAK-931 antitumor efficacy and immunity regulation. TAK-931 induce RS, generating senescence-like aneuploid cells, which highly expressed inflammatory cytokines and chemokines (senescence-associated secretory phenotype, SASP). In vivo multilayer-omics analyses in gene expression panel, immune panel, immunohistochemistry, RNA sequencing, and single-cell RNA sequencing reveal that the RS-mediated aneuploid cells generated by TAK-931 intensively activate inflammatory-related and senescence-associated pathways, resulting in accumulation of tumor-infiltrating immune cells and potent antitumor immunity and efficacy. Finally, the combination of TAK-931 and immune checkpoint inhibitors profoundly enhance antiproliferative activities. These findings suggest that TAK-931 has therapeutic antitumor properties and improved clinical benefits in combination with conventional immunotherapy.
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spelling pubmed-106574132023-11-18 CDC7 inhibition induces replication stress-mediated aneuploid cells with an inflammatory phenotype sensitizing tumors to immune checkpoint blockade Morita, Tomoko Yamamori Yu, Jie Kashima, Yukie Kamata, Ryo Yamamoto, Gaku Minamide, Tatsunori Mashima, Chiaki Yoshiya, Miyuki Sakae, Yuta Yamauchi, Toyohiro Hakozaki, Yumi Kageyama, Shun-ichiro Nakamura, Akito Lightcap, Eric Tanaka, Kosuke Niu, Huifeng Kannan, Karuppiah Ohashi, Akihiro Nat Commun Article Serine/threonine kinase, cell division cycle 7 (CDC7) is critical for initiating DNA replication. TAK-931 is a specific CDC7 inhibitor, which is a next-generation replication stress (RS) inducer. This study preclinically investigates TAK-931 antitumor efficacy and immunity regulation. TAK-931 induce RS, generating senescence-like aneuploid cells, which highly expressed inflammatory cytokines and chemokines (senescence-associated secretory phenotype, SASP). In vivo multilayer-omics analyses in gene expression panel, immune panel, immunohistochemistry, RNA sequencing, and single-cell RNA sequencing reveal that the RS-mediated aneuploid cells generated by TAK-931 intensively activate inflammatory-related and senescence-associated pathways, resulting in accumulation of tumor-infiltrating immune cells and potent antitumor immunity and efficacy. Finally, the combination of TAK-931 and immune checkpoint inhibitors profoundly enhance antiproliferative activities. These findings suggest that TAK-931 has therapeutic antitumor properties and improved clinical benefits in combination with conventional immunotherapy. Nature Publishing Group UK 2023-11-18 /pmc/articles/PMC10657413/ /pubmed/37980406 http://dx.doi.org/10.1038/s41467-023-43274-3 Text en © The Author(s) 2023 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Morita, Tomoko Yamamori
Yu, Jie
Kashima, Yukie
Kamata, Ryo
Yamamoto, Gaku
Minamide, Tatsunori
Mashima, Chiaki
Yoshiya, Miyuki
Sakae, Yuta
Yamauchi, Toyohiro
Hakozaki, Yumi
Kageyama, Shun-ichiro
Nakamura, Akito
Lightcap, Eric
Tanaka, Kosuke
Niu, Huifeng
Kannan, Karuppiah
Ohashi, Akihiro
CDC7 inhibition induces replication stress-mediated aneuploid cells with an inflammatory phenotype sensitizing tumors to immune checkpoint blockade
title CDC7 inhibition induces replication stress-mediated aneuploid cells with an inflammatory phenotype sensitizing tumors to immune checkpoint blockade
title_full CDC7 inhibition induces replication stress-mediated aneuploid cells with an inflammatory phenotype sensitizing tumors to immune checkpoint blockade
title_fullStr CDC7 inhibition induces replication stress-mediated aneuploid cells with an inflammatory phenotype sensitizing tumors to immune checkpoint blockade
title_full_unstemmed CDC7 inhibition induces replication stress-mediated aneuploid cells with an inflammatory phenotype sensitizing tumors to immune checkpoint blockade
title_short CDC7 inhibition induces replication stress-mediated aneuploid cells with an inflammatory phenotype sensitizing tumors to immune checkpoint blockade
title_sort cdc7 inhibition induces replication stress-mediated aneuploid cells with an inflammatory phenotype sensitizing tumors to immune checkpoint blockade
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10657413/
https://www.ncbi.nlm.nih.gov/pubmed/37980406
http://dx.doi.org/10.1038/s41467-023-43274-3
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