ArticleOncotarget2017
Combined inhibition of Wee1 and Chk1 gives synergistic DNA damage in S-phase due to distinct regulation of CDK activity and CDC45 loading.
Article in Oncotarget, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
37 citing papers in PubMed, 51 citations in OpenAlex.
- Combined Inhibition of Wee1 and Checkpoint Kinases Synergistically Provokes S-Phase Progression and Mitotic Entry, and Promotes Cell Death Under Heat Stress.Genes to cells : devoted to molecular & cellular mechanisms · 2026Article
- Ataxia telangiectasia mutated (ATM) kinase as a predictive biomarker in clinical oncology: implications for a precision treatment approach.Neoplasia (New York, N.Y.) · 2026Review
- Adaptive Replication Fork Acceleration by CDK1-Cyclin B1 Sustains Genome Duplication despite Impaired Origin Firing.bioRxiv : the preprint server for biology · 2026Article
- Rethinking the role of synergy calculations in the next century of drug combination discovery.Med (New York, N.Y.) · 2026Review
- Transcription termination counteracts DNA damage after WEE1 inhibition.Nucleic acids research · 2026Article
- WEE1 inhibition delays resistance to CDK4/6 inhibitor and antiestrogen treatment in ER+ MCF7 cells.NPJ systems biology and applications · 2025Article
- Embryonic Stem Cell-Specific Responses to DNA Replication Stress.bioRxiv : the preprint server for biology · 2025Article
- Characterizing functional DNA damage and response caused by the combination of CHK1 and WEE1 inhibitors in ovarian and breast cancer models.BJC reports · 2024Article
- FBH1 deficiency sensitizes cells to WEE1 inhibition by promoting mitotic catastrophe.DNA repair · 2024Article
- Centrosomes and associated proteins in pathogenesis and treatment of breast cancer.Frontiers in oncology · 2024Review
- Review
- Synthetic and Medicinal Chemistry Approaches Toward WEE1 Kinase Inhibitors and Its Degraders.ACS omega · 2023Review
- Article
- High abundance of CDC45 inhibits cell proliferation through elevation of HSPA6.Cell proliferation · 2022Article
- Targeting the DNA Damage Response for Cancer Therapy by Inhibiting the Kinase Wee1.Frontiers in oncology · 2022Review
- Review
- Recent Advances in Understanding the Mechanisms of Elemene in Reversing Drug Resistance in Tumor Cells: A Review.Molecules (Basel, Switzerland) · 2021Review
- High-throughput drug screening identifies the ATR-CHK1 pathway as a therapeutic vulnerability of CALR mutated hematopoietic cells.Blood cancer journal · 2021Article
- Article
- Acquired small cell lung cancer resistance to Chk1 inhibitors involves Wee1 up-regulation.Molecular oncology · 2021Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Recent studies have shown synergistic cytotoxic effects of simultaneous Chk1- and Wee1-inhibition. However, the mechanisms behind this synergy are not known. Here, we present a flow cytometry-based screen for compounds that cause increased DNA damage in S-phase when combined with the Wee1-inhibitor MK1775. Strikingly, the Chk1-inhibitors AZD7762 and LY2603618 were among the top candidate hits of 1664 tested compounds, suggesting that the synergistic cytotoxic effects are due to increased S-phase DNA damage. Combined Wee1- and Chk1-inhibition caused a strong synergy in induction of S-phase DNA damage and reduction of clonogenic survival. To address the underlying mechanisms, we developed a novel assay measuring CDK-dependent phosphorylations in single S-phase cells. Surprisingly, while Wee1-inhibition alone induced less DNA damage compared to Chk1-inhibition, Wee1-inhibition caused a bigger increase in S-phase CDK-activity. However, the loading of replication initiation factor CDC45 was more increased after Chk1- than Wee1-inhibition and further increased by the combined treatment, and thus correlated well with DNA damage. Therefore, when Wee1 alone is inhibited, Chk1 suppresses CDC45 loading and thereby limits the extent of unscheduled replication initiation and subsequent S-phase DNA damage, despite very high CDK-activity. These results can explain why combined treatment with Wee1- and Chk1-inhibitors gives synergistic anti-cancer effects.
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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.