ArticleCancer research2018
Mechanistic Distinctions between CHK1 and WEE1 Inhibition Guide the Scheduling of Triple Therapy with Gemcitabine.
Article in Cancer research, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
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.
The trial behind it
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
30 citing papers in PubMed, 42 citations in OpenAlex.
- Targeting DNA Damage Response and Immune Crosstalk in Cancer: Mechanistic Insights and Therapeutic Opportunities.International journal of molecular sciences · 2025Review
- Stochastic variation in the FOXM1 transcription program mediates replication stress tolerance.Molecular oncology · 2025Article
- CREB1-BCL2 drives mitochondrial resilience in RAS GAP-dependent breast cancer chemoresistance.Oncogene · 2025Article
- cAMP response element-binding protein: A credible cancer drug target.The Journal of pharmacology and experimental therapeutics · 2025Review
- Synthetic lethal combination of CHK1 and WEE1 inhibition for treatment of castration-resistant prostate cancer.Oncogene · 2024Article
- A Phase I Expansion Cohort Study Evaluating the Safety and Efficacy of the CHK1 Inhibitor LY2880070 with Low-dose Gemcitabine in Patients with Metastatic Pancreatic Adenocarcinoma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- Synthetic lethal combination of CHK1 and WEE1 inhibition for treatment of castration-resistant prostate cancer.Research square · 2023Article
- Targeting replication stress in cancer therapy.Nature reviews. Drug discovery · 2023Review
- A living biobank of matched pairs of patient-derived xenografts and organoids for cancer pharmacology.PloS one · 2023Article
- Clinical Trial Development in TP53-Mutated Locally Advanced and Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma.Journal of the National Cancer Institute · 2022Article
- Multiple-low-dose therapy: effective killing of high-grade serous ovarian cancer cells with ATR and CHK1 inhibitors.NAR cancer · 2022Article
- RASAL2 Confers Collateral MEK/EGFR Dependency in Chemoresistant Triple-Negative Breast Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2021Article
- Article
- Targeting cell cycle regulation via the G2-M checkpoint for synthetic lethality in melanoma.Cell cycle (Georgetown, Tex.) · 2021Review
- Store-Operated Calcium Entry: Shaping the Transcriptional and Epigenetic Landscape in Pancreatic Cancer.Cells · 2021Review
- Review
- Targeting Non-Oncogene Addiction for Cancer Therapy.Biomolecules · 2021Review
- Pharmacological Inhibition of WEE1 Potentiates the Antitumoral Effect of theInternational journal of molecular sciences · 2020Article
- A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target.Journal of hematology & oncology · 2020Review
- A novel siRNA-gemcitabine construct as a potential therapeutic for treatment of pancreatic cancer.NAR cancer · 2020Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 3 countries.
Funding
Abstract
Combination of cytotoxic therapy with emerging DNA damage response inhibitors (DDRi) has been limited by tolerability issues. However, the goal of most combination trials has been to administer DDRi with standard-of-care doses of chemotherapy. We hypothesized that mechanism-guided treatment scheduling could reduce the incidence of dose-limiting toxicities and enable tolerable multitherapeutic regimens. Integrative analyses of mathematical modeling and single-cell assays distinguished the synergy kinetics of WEE1 inhibitor (WEE1i) from CHEK1 inhibitor (CHK1i) by potency, spatiotemporal perturbation, and mitotic effects when combined with gemcitabine. These divergent properties collectively supported a triple-agent strategy, whereby a pulse of gemcitabine and CHK1i followed by WEE1i durably suppressed tumor cell growth. In xenografts, CHK1i exaggerated replication stress without mitotic CDK hyperactivation, enriching a geminin-positive subpopulation and intratumoral gemcitabine metabolite. Without overt toxicity, addition of WEE1i to low-dose gemcitabine and CHK1i was most effective in tumor control compared with single and double agents. Overall, our work provides quantitative insights into the mechanisms of DDRi chemosensitization, leading to the rational development of a tolerable multitherapeutic regimen.
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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.