ArticleMolecular cancer research : MCR2020
Inhibition of the ATR-CHK1 Pathway in Ewing Sarcoma Cells Causes DNA Damage and Apoptosis via the CDK2-Mediated Degradation of RRM2.
Article in Molecular cancer research : MCR, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 85 citations in OpenAlex.
- Not only as a Cullin3 ligase adaptor, SPOP may also act as a molecular bridge.Genes & diseases · 2027Review
- A system-level metastable model of cancer evolution: integrating replication stress, cell cycle deregulation and chromosomal instability.Annals of medicine · 2026Review
- Metal thiosemicarbazonates as dual mR2 RNR and colchicine-site tubulin inhibitors: from biochemical inhibition to mitotic arrest in MCF-7 breast cancer cells.Inorganic chemistry frontiers · 2026Article
- DNA replication stress and translational repression converge to drive CDK1- and caspase-dependent apoptosis in Ewing sarcoma.Oncogene · 2026Article
- Progress on the mechanism of Piezo1 in mechanical ventilation-induced lung injury.Journal of thoracic disease · 2026Review
- Autophagy impairs the sensitivity of Ewing sarcoma cells to PARP inhibitors.Cancer chemotherapy and pharmacology · 2026Article
- Hierarchies of resistance to DNA damage response inhibitors: from pathway restoration to replication stress tolerance.Experimental hematology & oncology · 2026Review
- Combined Inhibition of ATR and Ribonucleotide Reductase Induces Synergistic Antineoplastic Activity in Osteosarcoma Cells.Cancer reports (Hoboken, N.J.) · 2026Article
- Targeting replication stress in neuroblastoma by exploiting the synergistic potential of second generation RRM2 and CHK1 inhibitors.Cell death & disease · 2026Article
- Inflammatory myofibroblastic tumour: unravelling the interplay of inflammation, kinase signalling, and therapeutic resistance.Frontiers in oncology · 2026Review
- Pathway for the Development of ATR Inhibitors in Pediatric Malignancies: An ACCELERATE Multistakeholder Analysis.JCO precision oncology · 2026Review
- Lipopolysaccharide-induced M1-type Macrophages Enhance T Cell Activity and Promote the Apoptosis of Hepatocellular Carcinoma Cells.Current topics in medicinal chemistry · 2026Article
- Identification of a Proteolysis-Targeting-Chimera that Addresses Activated Checkpoint Kinase-1 Reveals its Non-Catalytic Functions in Tumor Cells.Angewandte Chemie (International ed. in English) · 2025Article
- The Puzzle of Genetic Stability and Chromosomal Copy Number Alterations for the Therapy of Ewing Sarcoma.Cancers · 2025Review
- New Approaches to Investigate Novel Agents in Ewing Sarcoma: A Report From the Children's Oncology Group Bone Tumor Committee.Pediatric blood & cancer · 2025Review
- WEE1 inhibitor exerts synergistic effect with KRAS G12C inhibitor via MYBL2-RRM2 axis in KRASCell death & disease · 2025Article
- Unveiling the Therapeutic Potential of Targeting RRM2 in Hepatocellular Carcinoma: An Integrated In Silico and In Vitro Study.Functional & integrative genomics · 2025Article
- Histone Deacetylase Inhibitors Target DNA Replication Regulators and Replication Stress in Ewing Sarcoma Cells.Cancer research communications · 2025Article
- Combined inhibition of ribonucleotide reductase and WEE1 induces synergistic anticancer activity in Ewing's sarcoma cells.BMC cancer · 2025Article
- Arginine methylation regulates Ewing sarcoma cell viability in aFrontiers in oncology · 2025Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Inhibition of ribonucleotide reductase (RNR), the rate-limiting enzyme in the synthesis of deoxyribonucleotides, causes DNA replication stress and activates the ataxia telangiectasia and rad3-related protein (ATR)-checkpoint kinase 1 (CHK1) pathway. Notably, a number of different cancers, including Ewing sarcoma tumors, are sensitive to the combination of RNR and ATR-CHK1 inhibitors. However, multiple, overlapping mechanisms are reported to underlie the toxicity of ATR-CHK1 inhibitors, both as single agents and in combination with RNR inhibitors, toward cancer cells. Here, we identified a feedback loop in Ewing sarcoma cells in which inhibition of the ATR-CHK1 pathway depletes RRM2, the small subunit of RNR, and exacerbates the DNA replication stress and DNA damage caused by RNR inhibitors. Mechanistically, we identified that the inhibition of ATR-CHK1 activates CDK2, which targets RRM2 for degradation via the proteasome. Similarly, activation of CDK2 by inhibition or knockdown of the WEE1 kinase also depletes RRM2 and causes DNA damage and apoptosis. Moreover, we show that the concurrent inhibition of ATR and WEE1 has a synergistic effect in Ewing sarcoma cells. Overall, our results provide novel insight into the response to DNA replication stress, as well as a rationale for targeting the ATR, CHK1, and WEE1 pathways, in Ewing sarcoma tumors. IMPLICATIONS: Targeting the ATR, CHK1, and WEE1 kinases in Ewing sarcoma cells activates CDK2 and increases DNA replication stress by promoting the proteasome-mediated degradation of RRM2.
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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.