ArticleMolecular cancer2009
Discovery of gene expression-based pharmacodynamic biomarker for a p53 context-specific anti-tumor drug Wee1 inhibitor.
Article in Molecular cancer, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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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
44 citing papers in PubMed, 71 citations in OpenAlex.
- Novel Combinations of Immunotherapies or DNA Damage Repair Inhibitors in Platinum-Refractory Extensive-Stage Small Cell Lung Cancer: The Phase II BALTIC Study.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Trial
- Clinical Efficacy and Molecular Response Correlates of the WEE1 Inhibitor Adavosertib Combined with Cisplatin in Patients with Metastatic Triple-Negative Breast Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2021Trial
- Wee1 inhibition by MK-1775 leads to tumor inhibition and enhances efficacy of gemcitabine in human sarcomas.PloS one · 2013Trial
- Chemogenomic maps reveal a PRDX1-dependent iron-damage axis in the DNA damage response.Nature chemical biology · 2026Article
- WEE1 kinase in cancer: Molecular mechanisms and inhibitor insights.EXCLI journal · 2026Review
- Targeting WEE1 kinase as a p53-independent therapeutic strategy in high-risk and relapsed acute lymphoblastic leukemia.Cancer cell international · 2023Article
- MicroRNA-dependent inhibition of WEE1 controls cancer stem-like characteristics and malignant behavior in ovarian cancer.Molecular therapy. Nucleic acids · 2022Article
- Review
- Facilitating Drug Discovery in Breast Cancer by Virtually Screening Patients Using In Vitro Drug Response Modeling.Cancers · 2021Article
- Computational study of zebrafish immune-targeted microarray data for prediction of preventive drug candidates.Veterinary research forum : an international quarterly journal · 2021Article
- Wee1 Kinase Inhibitor AZD1775 Effectively Sensitizes Esophageal Cancer to Radiotherapy.Clinical cancer research : an official journal of the American Association for Cancer Research · 2020Article
- mTOR inhibition overcomes primary and acquired resistance to Wee1 inhibition by augmenting replication stress in epithelial ovarian cancers.American journal of cancer research · 2020Article
- State-of-the-art strategies for targeting the DNA damage response in cancer.Nature reviews. Clinical oncology · 2019Review
- Discovery of novel wee1 inhibitors via structure-based virtual screening and biological evaluation.Journal of computer-aided molecular design · 2018Article
- AZD1775 Increases Sensitivity to Olaparib and Gemcitabine in Cancer Cells with p53 Mutations.Cancers · 2018Article
- Activation of WEE1 confers resistance to PI3K inhibition in glioblastoma.Neuro-oncology · 2018Article
- Wee1 Inhibitor AZD1775 Combined with Cisplatin Potentiates Anticancer Activity against Gastric Cancer by Increasing DNA Damage and Cell Apoptosis.BioMed research international · 2018Article
- Regulation of G2/M Transition by Inhibition of WEE1 and PKMYT1 Kinases.Molecules (Basel, Switzerland) · 2017Review
- Novel DNA targeted therapies for head and neck cancers: clinical potential and biomarkers.Oncotarget · 2017Review
- A Small-Molecule Inhibitor of WEE1, AZD1775, Synergizes with Olaparib by Impairing Homologous Recombination and Enhancing DNA Damage and Apoptosis in Acute Leukemia.Molecular cancer therapeutics · 2017Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundWee1 is a tyrosine kinase regulating S-G2 cell cycle transition through the inactivating phosphorylation of CDC2. The inhibition of Wee1 kinase by a selective small molecule inhibitor significantly enhances the anti-tumor efficacy of DNA damaging agents, specifically in p53 negative tumors by abrogating S-G2 checkpoints, while normal cells with wild-type p53 are not severely damaged due to the intact function of the G1 checkpoint mediated by p53. Since the measurement of mRNA expression requires a very small amount of biopsy tissue and is highly quantitative, the development of a pharmacodynamic (PD) biomarker leveraging mRNA expression is eagerly anticipated in order to estimate target engagement of anti-cancer agents.
resultsIn order to find the Wee1 inhibition signature, mRNA expression profiling was first performed in both p53 positive and negative cancer cell lines treated with gemcitabine and a Wee1 inhibitor, MK-1775. We next carried out mRNA expression profiling of skin samples derived from xenograft models treated with the Wee1 inhibitor to identify a Wee1 inhibitor-regulatory gene set. Then, the genes that were commonly modulated in both cancer cell lines and rat skin samples were extracted as a Wee1 inhibition signature that could potentially be used as a PD biomarker independent of p53 status. The expression of the Wee1 inhibition signature was found to be regulated in a dose-dependent manner by the Wee1 inhibitor, and was significantly correlated with the inhibition level of a direct substrate, phosphorylated-CDC2. Individual genes in this Wee1 inhibition signature are known to regulate S-G2 cell cycle progression or checkpoints, which is consistent with the mode-of-action of the Wee1 inhibitor.
conclusionWe report here the identification of an mRNA gene signature that was specifically changed by gemcitabine and Wee1 inhibitor combination treatment by molecular profiling. Given the common regulation of expression in both xenograft tumors and animal skin samples, the data suggest that the Wee1 inhibition gene signature might be utilized as a quantitative PD biomarker in both tumors and surrogate tissues, such as skin and hair follicles, in human clinical trials.
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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.