ArticleOncotarget2016
A subset of cancer cell lines is acutely sensitive to the Chk1 inhibitor MK-8776 as monotherapy due to CDK2 activation in S phase.
Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
What it found
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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.
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.
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Who cites it
46 citing papers in PubMed, 74 citations in OpenAlex.
- Trial
- The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor-Positive Metastatic Breast Cancer.Cancer discovery · 2020Trial
- Dual CHK1 and WNT Inhibition as a Synergistic Therapy for Gastrointestinal Neuroendocrine Carcinoma.Cancer research communications · 2026Article
- Exploring a specialized lactylation pattern to predict the prognosis and sensitivity of immunotherapy in breast cancer via machine learning.Breast cancer (Tokyo, Japan) · 2026Article
- Chloroquine Potentiates the Chemotherapeutic Effect of Carboplatin and ATR/Chk1 Inhibitors by Increasing the Replication Stress.International journal of molecular sciences · 2026Article
- Aurora B inhibitors promote RB hypophosphorylation and senescence independent of p53-dependent CDK2/4 inhibition.Cell death & disease · 2024Article
- The CDK4/6 inhibitor revolution - a game-changing era for breast cancer treatment.Nature reviews. Clinical oncology · 2024Review
- Harnessing machine learning to find synergistic combinations for FDA-approved cancer drugs.Scientific reports · 2024Article
- Emerging systemic therapy options beyond CDK4/6 inhibitors for hormone receptor-positive HER2-negative advanced breast cancer.NPJ breast cancer · 2023Review
- CDK4/6 Inhibition in the Metastatic Setting: Where Are We Headed?Current treatment options in oncology · 2023Review
- Nuclear pCHK1 as a potential biomarker of increased sensitivity to ATR inhibition.The Journal of pathology · 2023Article
- Regulation of CHK1 inhibitor resistance by a c-Rel and USP1 dependent pathway.The Biochemical journal · 2022Article
- Up-regulation of the PI3K/AKT and RHO/RAC/PAK signalling pathways in CHK1 inhibitor resistant Eµ-Myc lymphoma cells.The Biochemical journal · 2022Article
- Inhibition of Protein Synthesis Induced by CHK1 Inhibitors Discriminates Sensitive from Resistant Cancer Cells.ACS pharmacology & translational science · 2021Article
- Activation of CDC25A phosphatase is limited by CDK2/cyclin A-mediated feedback inhibition.Cell cycle (Georgetown, Tex.) · 2021Article
- CDK2-Mediated Upregulation of TNFα as a Mechanism of Selective Cytotoxicity in Acute Leukemia.Cancer research · 2021Article
- Comparative Activity and Off-Target Effects in Cells of the CHK1 Inhibitors MK-8776, SRA737, and LY2606368.ACS pharmacology & translational science · 2021Article
- Acquired small cell lung cancer resistance to Chk1 inhibitors involves Wee1 up-regulation.Molecular oncology · 2021Article
- Sensitivity of cells to ATR and CHK1 inhibitors requires hyperactivation of CDK2 rather than endogenous replication stress or ATM dysfunction.Scientific reports · 2021Article
- Mus81-Eme1-dependent aberrant processing of DNA replication intermediates in mitosis impairs genome integrity.Science advances · 2020Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
DNA damage activates Checkpoint kinase 1 (Chk1) to halt cell cycle progression thereby preventing further DNA replication and mitosis until the damage has been repaired. Consequently, Chk1 inhibitors have emerged as promising anticancer therapeutics in combination with DNA damaging drugs, but their single agent activity also provides a novel approach that may be particularly effective in a subset of patients. From analysis of a large panel of cell lines, we demonstrate that 15% are very sensitive to the Chk1 inhibitor MK-8776. Upon inhibition of Chk1, sensitive cells rapidly accumulate DNA double-strand breaks in S phase in a CDK2- and cyclin A-dependent manner. In contrast, resistant cells can continue to grow for at least 7 days despite continued inhibition of Chk1. Resistance can be circumvented by inhibiting Wee1 kinase and thereby directly activating CDK2. Hence, sensitivity to Chk1 inhibition is regulated upstream of CDK2 and correlates with accumulation of CDC25A. We conclude that cells poorly tolerate CDK2 activity in S phase and that a major function of Chk1 is to ensure it remains inactive. Indeed, inhibitors of CDK1 and CDK2 arrest cells in G1 or G2, respectively, but do not prevent progression through S phase demonstrating that neither kinase is required for S phase progression. Inappropriate activation of CDK2 in S phase underlies the sensitivity of a subset of cell lines to Chk1 inhibitors, and this may provide a novel therapeutic opportunity for appropriately stratified patients.
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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.