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

Tomoko Yamamori Morita, Jie Yu, Yukie Kashima, Ryo Kamata, Gaku Yamamoto, Tatsunori Minamide, Chiaki Mashima, Miyuki Yoshiya, Yuta Sakae, Toyohiro Yamauchi, Yumi Hakozaki, Shun-ichiro Kageyama, Akito Nakamura, Eric Lightcap, Kosuke Tanaka, Huifeng Niu, Karuppiah Kannan and Akihiro Ohashi ()
Additional contact information
Tomoko Yamamori Morita: Exploratory Oncology Research & Clinical Trial Center, National Cancer Center
Jie Yu: Oncology Drug Discovery Unit, Takeda Development Center Americas (TDCA), Inc.
Yukie Kashima: Exploratory Oncology Research & Clinical Trial Center, National Cancer Center
Ryo Kamata: Exploratory Oncology Research & Clinical Trial Center, National Cancer Center
Gaku Yamamoto: Exploratory Oncology Research & Clinical Trial Center, National Cancer Center
Tatsunori Minamide: Exploratory Oncology Research & Clinical Trial Center, National Cancer Center
Chiaki Mashima: Exploratory Oncology Research & Clinical Trial Center, National Cancer Center
Miyuki Yoshiya: Exploratory Oncology Research & Clinical Trial Center, National Cancer Center
Yuta Sakae: Exploratory Oncology Research & Clinical Trial Center, National Cancer Center
Toyohiro Yamauchi: Exploratory Oncology Research & Clinical Trial Center, National Cancer Center
Yumi Hakozaki: Exploratory Oncology Research & Clinical Trial Center, National Cancer Center
Shun-ichiro Kageyama: National Cancer Center Hospital East
Akito Nakamura: Oncology Drug Discovery Unit, Takeda Development Center Americas (TDCA), Inc.
Eric Lightcap: Oncology Drug Discovery Unit, Takeda Development Center Americas (TDCA), Inc.
Kosuke Tanaka: Exploratory Oncology Research & Clinical Trial Center, National Cancer Center
Huifeng Niu: Oncology Translational Science., TDCA, Inc.
Karuppiah Kannan: Oncology Therapeutic Area Unit, TDCA, Inc.
Akihiro Ohashi: Exploratory Oncology Research & Clinical Trial Center, National Cancer Center

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract 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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-43274-3 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43274-3

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-43274-3

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().