ArticleProceedings of the National Academy of Sciences of the United States of America2015
A haploid genetic screen identifies the G1/S regulatory machinery as a determinant of Wee1 inhibitor sensitivity.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers, 1 of them a synthesis that pooled it.
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Who cites it
44 citing papers in PubMed, 1 synthesis or guideline pooled it, 66 citations in OpenAlex.
- An update of predictive biomarkers related to WEE1 inhibition in cancer therapy.Journal of cancer research and clinical oncology · 2024Pooled it
- 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
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- Targeting WEE1 in ARID1A/TP53 Concurrent Mutant Colorectal Cancer by Exploiting R-Loop Accumulation and DNA Repair Deficiencies.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- WEE1 inhibitors trigger GCN2-mediated activation of the integrated stress response.Nature communications · 2025Article
- WEE1 inhibition delays resistance to CDK4/6 inhibitor and antiestrogen treatment in ER+ MCF7 cells.NPJ systems biology and applications · 2025Article
- Spatial transcriptomics exploration of the primary neuroblastoma microenvironment in archived FFPE samples unveils novel paracrine interactions.The Journal of pathology · 2025Article
- Targeting WEE1 Kinase for Breast Cancer Therapeutics: An Update.International journal of molecular sciences · 2025Review
- High WEE1 expression is independently linked to poor survival in multiple myeloma.Blood cancer journal · 2025Article
- High WEE1 expression is independently linked to poor survival in multiple myeloma.bioRxiv : the preprint server for biology · 2024Article
- GCN2 is a determinant of the response to WEE1 kinase inhibition in small-cell lung cancer.Cell reports · 2024Article
- Homologous recombination proficient subtypes of high-grade serous ovarian cancer: treatment options for a poor prognosis group.Frontiers in oncology · 2024Review
- FBXW7-loss Sensitizes Cells to ATR Inhibition Through Induced Mitotic Catastrophe.Cancer research communications · 2023Article
- The Adaptive Mechanisms and Checkpoint Responses to a Stressed DNA Replication Fork.International journal of molecular sciences · 2023Review
- Combination of PARP and WEE1 inhibitorsOncology reports · 2023Article
- SIRT1 deacetylates WEE1 and sensitizes cancer cells to WEE1 inhibition.Nature chemical biology · 2023Article
- Sister chromatid exchanges induced by perturbed replication can form independently of BRCA1, BRCA2 and RAD51.Nature communications · 2022Article
- PEAK1 Y635 phosphorylation regulates cell migration through association with Tensin3 and integrins.The Journal of cell biology · 2022Article
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Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The Wee1 cell cycle checkpoint kinase prevents premature mitotic entry by inhibiting cyclin-dependent kinases. Chemical inhibitors of Wee1 are currently being tested clinically as targeted anticancer drugs. Wee1 inhibition is thought to be preferentially cytotoxic in p53-defective cancer cells. However, TP53 mutant cancers do not respond consistently to Wee1 inhibitor treatment, indicating the existence of genetic determinants of Wee1 inhibitor sensitivity other than TP53 status. To optimally facilitate patient selection for Wee1 inhibition and uncover potential resistance mechanisms, identification of these currently unknown genes is necessary. The aim of this study was therefore to identify gene mutations that determine Wee1 inhibitor sensitivity. We performed a genome-wide unbiased functional genetic screen in TP53 mutant near-haploid KBM-7 cells using gene-trap insertional mutagenesis. Insertion site mapping of cells that survived long-term Wee1 inhibition revealed enrichment of G1/S regulatory genes, including SKP2, CUL1, and CDK2. Stable depletion of SKP2, CUL1, or CDK2 or chemical Cdk2 inhibition rescued the γ-H2AX induction and abrogation of G2 phase as induced by Wee1 inhibition in breast and ovarian cancer cell lines. Remarkably, live cell imaging showed that depletion of SKP2, CUL1, or CDK2 did not rescue the Wee1 inhibition-induced karyokinesis and cytokinesis defects. These data indicate that the activity of the DNA replication machinery, beyond TP53 mutation status, determines Wee1 inhibitor sensitivity, and could serve as a selection criterion for Wee1-inhibitor eligible patients. Conversely, loss of the identified S-phase genes could serve as a mechanism of acquired resistance, which goes along with development of severe genomic instability.
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