ArticleCell death discovery2022
CDC7 kinase (DDK) inhibition disrupts DNA replication leading to mitotic catastrophe in Ewing sarcoma.
Article in Cell death discovery, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 19 citations in OpenAlex.
- Thieno[3,2-International journal of molecular sciences · 2026Review
- DNA replication stress and translational repression converge to drive CDK1- and caspase-dependent apoptosis in Ewing sarcoma.Oncogene · 2026Article
- Autophagy impairs the sensitivity of Ewing sarcoma cells to PARP inhibitors.Cancer chemotherapy and pharmacology · 2026Article
- CDC7 is a targetable regulator of advanced prostate cancer.Scientific reports · 2025Article
- Identifying TP53RK as a key regulator of colorectal cancer survival and a potential therapeutic target.Scientific reports · 2025Article
- New Approaches to Investigate Novel Agents in Ewing Sarcoma: A Report From the Children's Oncology Group Bone Tumor Committee.Pediatric blood & cancer · 2025Review
- Histone Deacetylase Inhibitors Target DNA Replication Regulators and Replication Stress in Ewing Sarcoma Cells.Cancer research communications · 2025Article
- The lncRNA DUBR is regulated by CTCF and coordinates chromatin landscape and gene expression in hematopoietic cells.Nucleic acids research · 2025Article
- The crosstalk between senescence, tumor, and immunity: molecular mechanism and therapeutic opportunities.MedComm · 2025Review
- Arginine methylation regulates Ewing sarcoma cell viability in aFrontiers in oncology · 2025Article
- STAG2 loss in Ewing sarcoma alters enhancer-promoter contacts dependent and independent of EWS::FLI1.EMBO reports · 2024Article
- DBF4, not DRF1, is the crucial regulator of CDC7 kinase at replication forks.The Journal of cell biology · 2024Article
- Enhancing Standard of Care Chemotherapy Efficacy Using DNA-Dependent Protein Kinase (DNA-PK) Inhibition in Preclinical Models of Ewing Sarcoma.Molecular cancer therapeutics · 2024Article
- The prognostic significance and potential mechanism of DBF4 zinc finger in hepatocellular carcinoma.Scientific reports · 2024Article
- Review
- Activator Protein-1 (AP-1) Signaling Inhibits the Growth of Ewing Sarcoma Cells in Response to DNA Replication Stress.Cancer research communications · 2023Article
- Identifying CDC7 as a synergistic target of chemotherapy in resistant small-cell lung cancer via CRISPR/Cas9 screening.Cell death discovery · 2023Article
- Flow Cytometry Detection of Anthracycline-Treated Breast Cancer Cells: An Optimized Protocol.Current issues in molecular biology · 2022Article
- WEE1 inhibition augments CDC7 (DDK) inhibitor-induced cell death in Ewing sarcoma by forcing premature mitotic entry and mitotic catastrophe.Cancer research communications · 2022Article
- CDC7 Expression in Selected Odontogenic Tumors.International journal of dentistry · 2022Article
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
Ewing sarcoma is the second most common bone malignancy in children and adolescents. In recent years, a large body of evidence has emerged that suggests Ewing tumors harbor large amounts of replication stress (RS). CDC7, also known as DDK (DBF4-dependent kinase), is a serine/threonine kinase that is involved in a diverse array of cellular functions including the regulation of DNA replication initiation and activation of the RS response. Due to DDK's diverse roles during replication, coupled with the fact that there is an increased level of RS within Ewing tumors, we hypothesized that Ewing sarcoma cells would be particularly vulnerable to DDK inhibition. Here, we report that DDK inhibition resulted a significant reduction in cell viability and the induction of apoptosis, specifically in Ewing sarcoma cells. Treatment with DDK inhibitors dramatically reduced the rate of replication, prolonged S-phase, and led to a pronounced increase in phospho-CDC2 (Y15), indicating delay of mitotic entry. The induction of cell death corresponded to mitotic exit and G1 entry, suggesting improper mitotic progression. In accordance with this, we find that DDK inhibition caused premature mitotic entry resulting in mitotic abnormalities such as anaphase bridges, lagging chromosomes, and cells with >2 poles in Ewing sarcoma cells. This abnormal progression through mitosis resulted in mitotic catastrophe as evidenced by the formation of micronuclei and induction of DNA damage. Together, these findings suggest that DDK activity is required for the faithful and timely completion of DNA replication in Ewing cells and that DDK inhibition may present a viable therapeutic strategy for the treatment of Ewing sarcoma.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.