ArticleOncogenesis2020
Overexpression of Cyclin E1 or Cdc25A leads to replication stress, mitotic aberrancies, and increased sensitivity to replication checkpoint inhibitors.
Article in Oncogenesis, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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Who cites it
59 citing papers in PubMed, 92 citations in OpenAlex.
- The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial.Nature communications · 2024Trial
- Not only as a Cullin3 ligase adaptor, SPOP may also act as a molecular bridge.Genes & diseases · 2027Review
- CCNE1: A Cell Cycle Regulator That Influences Tumor Progression.Cancer medicine · 2026Review
- CIZ1 regulates G1 length and the CDK threshold for initiation of DNA replication to prevent DNA replication stress.Nucleic acids research · 2026Article
- Replication origin firing capacity indicates ATR inhibitor sensitivity.Nature communications · 2026Article
- Cyclin E modulates vulnerability to CDC7 kinase inhibition.Oncogenesis · 2026Article
- Distinct mechanisms of replication stress induced by oncogenic RAS and cyclin E1 converge on R-loop-dependent fork reversal.Nature communications · 2026Article
- CHAMP1 complex promotes heterochromatin assembly and reduces replication stress.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Biomarker-Driven Treatments for Ovarian Cancer: Moving Beyond HRD?International journal of women's health · 2026Review
- Targeting ATR offers multifaceted treatment strategies involving RAD51-mediated compensatory DNA repair in bladder cancer.Journal of experimental & clinical cancer research : CR · 2025Article
- CIP2A mediates mitotic recruitment of SLX4/MUS81/XPF to resolve replication stress-induced DNA lesions.Nature communications · 2025Article
- Discovery of a bifunctional PKMYT1-targeting PROTAC empowered by AI-generation.Nature communications · 2025Article
- WEE1 inhibitors trigger GCN2-mediated activation of the integrated stress response.Nature communications · 2025Article
- Molecular profiling of endometrial cancer in Martinique reveals frequent CCNE1 amplification in poor prognosis tumors.Scientific reports · 2025Article
- WEE1 inhibition delays resistance to CDK4/6 inhibitor and antiestrogen treatment in ER+ MCF7 cells.NPJ systems biology and applications · 2025Article
- Research progress of DUB enzyme in breast cancer.Clinical and experimental medicine · 2025Review
- Azenosertib Is a Potent and Selective WEE1 Kinase Inhibitor with Broad Antitumor Activity Across a Range of Solid Tumors.Molecular cancer therapeutics · 2025Article
- DNA repair and the contribution to chemotherapy resistance.Genome medicine · 2025Review
- Cyclin E1 overexpression sensitizes ovarian cancer cells to WEE1 and PLK1 inhibition.Oncogene · 2025Article
- Profiling the Activity of the Potent and Highly Selective CDK2 Inhibitor BLU-222 Reveals Determinants of Response in CCNE1-Aberrant Ovarian and Endometrial Tumors.Cancer research · 2025Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Oncogene-induced replication stress, for instance as a result of Cyclin E1 overexpression, causes genomic instability and has been linked to tumorigenesis. To survive high levels of replication stress, tumors depend on pathways to deal with these DNA lesions, which represent a therapeutically actionable vulnerability. We aimed to uncover the consequences of Cyclin E1 or Cdc25A overexpression on replication kinetics, mitotic progression, and the sensitivity to inhibitors of the WEE1 and ATR replication checkpoint kinases. We modeled oncogene-induced replication stress using inducible expression of Cyclin E1 or Cdc25A in non-transformed RPE-1 cells, either in a TP53 wild-type or TP53-mutant background. DNA fiber analysis showed Cyclin E1 or Cdc25A overexpression to slow replication speed. The resulting replication-derived DNA lesions were transmitted into mitosis causing chromosome segregation defects. Single cell sequencing revealed that replication stress and mitotic defects upon Cyclin E1 or Cdc25A overexpression resulted in genomic instability. ATR or WEE1 inhibition exacerbated the mitotic aberrancies induced by Cyclin E1 or Cdc25A overexpression, and caused cytotoxicity. Both these phenotypes were exacerbated upon p53 inactivation. Conversely, downregulation of Cyclin E1 rescued both replication kinetics, as well as sensitivity to ATR and WEE1 inhibitors. Taken together, Cyclin E1 or Cdc25A-induced replication stress leads to mitotic segregation defects and genomic instability. These mitotic defects are exacerbated by inhibition of ATR or WEE1 and therefore point to mitotic catastrophe as an underlying mechanism. Importantly, our data suggest that Cyclin E1 overexpression can be used to select patients for treatment with replication checkpoint inhibitors.
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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.