| RRC ID |
78857
|
| 著者 |
Morita TY, Yu J, Kashima Y, Kamata R, Yamamoto G, Minamide T, Mashima C, Yoshiya M, Sakae Y, Yamauchi T, Hakozaki Y, Kageyama SI, Nakamura A, Lightcap E, Tanaka K, Niu H, Kannan K, Ohashi A.
|
| タイトル |
CDC7 inhibition induces replication stress-mediated aneuploid cells with an inflammatory phenotype sensitizing tumors to immune checkpoint blockade.
|
| ジャーナル |
Nat Commun
|
| 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.
|
| 巻・号 |
14(1)
|
| ページ |
7490
|
| 公開日 |
2023-11-18
|
| DOI |
10.1038/s41467-023-43274-3
|
| PII |
10.1038/s41467-023-43274-3
|
| PMID |
37980406
|
| PMC |
PMC10657413
|
| MeSH |
Aneuploidy
Cell Cycle Proteins* / metabolism
Humans
Immune Checkpoint Inhibitors
Neoplasms* / drug therapy
Neoplasms* / genetics
Protein Serine-Threonine Kinases / metabolism
|
| リソース情報 |
| ヒト・動物細胞 |
HeLa
A549 |
