ArticleCell genomics2025
Identification of targetable vulnerabilities of PLK1-overexpressing cancers by synthetic dosage lethality.
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Article in Cell genomics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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5citing papers in PubMed
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Who cites it
5 citing papers in PubMed.
- Expanding Synthetic Lethality in DNA Damage Response-Defective Cancers Through Stress Phenotype-Guided Kinase Targeting.International journal of molecular sciences · 2026Review
- Bosutinib Inhibits USP9X to Suppress the Proliferation, Migration, Angiogenesis and Glycolysis of Hepatocellular Carcinoma Cells by Deubiquitinating PLK1.Clinical and experimental pharmacology & physiology · 2026Article
- Synthetic lethality in cancer: mechanism exploration and therapeutic applications.Cell communication and signaling : CCS · 2026Review
- Synthetic lethality in cancer therapy: Mechanisms, models and clinical translation for overcoming therapeutic resistance.Clinical and translational medicine · 2026Review
- IGF2BP2 Deficiency in Macrophages Impairs Migration, Reprograms Metabolism, and Limits Tumor Progression.International journal of biological sciences · 2026Article
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Authors and funding
56 authors.
Chelsea E CunninghamDepartment of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Frederick S VizeacoumarDepartment of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Yue ZhangDepartment of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Liliia KyrylenkoDepartment of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Simon BothDepartment of Pharmacy, Pharmaceutical Biology, Saarland University, PharmaScienceHub, 66123 Saarbrücken, Germany.
Vincent MarandaDepartment of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
He DongDepartment of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Jared D W PriceDepartment of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Peng GaoGlobal Institute for Food Security, University of Saskatchewan, Saskatoon, SK S7N 4L8, Canada; Agriculture and Agri-Food Canada, Saskatoon Research and Development Centre, 107 Science Place, Saskatoon, SK S7N 0X2, Canada.
Konrad WagnerAntiviral & Antivirulence Drugs (AVID), Helmholtz Institute for Pharmaceutical Research, Saarland (HIPS), Helmholtz Centre for Infection Research (HZI) and Department of Pharmacy, Saarland University, 66123 Saarbrücken, Germany.
Yingwen WuAntiviral & Antivirulence Drugs (AVID), Helmholtz Institute for Pharmaceutical Research, Saarland (HIPS), Helmholtz Centre for Infection Research (HZI) and Department of Pharmacy, Saarland University, 66123 Saarbrücken, Germany.
Mary Lazell-WrightDepartment of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Ashtalakshmi GanapathysamyDepartment of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Rithik HariDepartment of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Kalpana K BhanumathyDepartment of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Connor DenomyDepartment of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Anjali SaxenaDepartment of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Jeff P VizeacoumarDepartment of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Alain Morejon MoralesDepartment of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Faizaan KhanDepartment of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Shayla MosleyDepartment of Oncology, University of Alberta, Edmonton, AB T6G 1Z2, Canada.
Angie ChenDepartment of Oncology, University of Alberta, Edmonton, AB T6G 1Z2, Canada.
Tetiana KatriiDepartment of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Ben G E ZollerAntiviral & Antivirulence Drugs (AVID), Helmholtz Institute for Pharmaceutical Research, Saarland (HIPS), Helmholtz Centre for Infection Research (HZI) and Department of Pharmacy, Saarland University, 66123 Saarbrücken, Germany.
Karthic RajamanickamDepartment of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Prachi WalkeDepartment of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; Department of Anatomy, Physiology, and Pharmacology, University of Saskatchewan, and Cameco MS Neuroscience Research Centre, 701 Queen St., Saskatoon, SK S7K 0M7, Canada.
Lihui GongDepartment of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Hardikkumar PatelDepartment of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Hussain ElhasasnaDepartment of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Renuka DahiyaDepartment of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Omar AbuhusseinDepartment of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Anton DmitrievDepartment of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Tanya FreywaldDepartment of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Erika Prando MunhozDepartment of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Eytan RuppinCancer Data Science Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Center for Bioinformatics and Computational Biology and Department of Computer Sciences, University of Maryland, College Park, MD 20742, USA.
Joo Sang LeeCancer Data Science Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Center for Bioinformatics and Computational Biology and Department of Computer Sciences, University of Maryland, College Park, MD 20742, USA; Department of Precision Medicine, School of Medicine and Department of Artificial Intelligence, Sungkyunkwan University, Suwon 16419, Republic of Korea.
Katharina RoxDepartment of Chemical Biology (CBIO), Helmholtz Center for Infection Research (HZI), Inhoffenstrasse 7, 38124 Braunschweig, Germany.
Martin KoebelDepartment of Pathology, University of Calgary, Calgary, AB, Canada.
Laura HopkinsDepartment of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Cheng Han LeeDepartment of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada.
Sunil YadavDepartment of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Gilles GasparoniDepartment of Genetics, Saarland University, Saarbrücken, Germany.
Jörn WalterDepartment of Genetics, Saarland University, Saarbrücken, Germany.
Anand KrishnanDepartment of Anatomy, Physiology, and Pharmacology, University of Saskatchewan, and Cameco MS Neuroscience Research Centre, 701 Queen St., Saskatoon, SK S7K 0M7, Canada.
Raju DatlaGlobal Institute for Food Security, University of Saskatchewan, Saskatoon, SK S7N 4L8, Canada.
Behzad ToosiWestern College of Veterinary Medicine, University of Saskatchewan, Room 2343, 52 Campus Drive, Saskatoon S7N 5B4, Canada.
Kristi BakerDepartment of Oncology, University of Alberta, Edmonton, AB T6G 1Z2, Canada.
Jalna MeensPrincess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
David W CesconPrincess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Laurie AillesPrincess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Scot C LearyDepartment of Biochemistry, Microbiology, and Immunology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Yuliang WuDepartment of Biochemistry, Microbiology, and Immunology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Martin EmptingAntiviral & Antivirulence Drugs (AVID), Helmholtz Institute for Pharmaceutical Research, Saarland (HIPS), Helmholtz Centre for Infection Research (HZI) and Department of Pharmacy, Saarland University, 66123 Saarbrücken, Germany. Electronic address: martin.empting@helmholtz-hips.de.
Alexandra K KiemerDepartment of Pharmacy, Pharmaceutical Biology, Saarland University, PharmaScienceHub, 66123 Saarbrücken, Germany; Center for Gender-Specific Biology and Medicine (CGBM), 66421 Homburg, Germany. Electronic address: pharm.bio.kiemer@uni-saarland.de.
Andrew FreywaldDepartment of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada. Electronic address: andrew.freywald@usask.ca.
Franco J VizeacoumarDepartment of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; Cancer Research, Saskatchewan Cancer Agency, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada. Electronic address: franco.vizeacoumar@usask.ca.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Chromosomal instability (CIN) drives tumor heterogeneity, complicating cancer therapy. Although Polo-like kinase 1 (PLK1) overexpression induces CIN, direct inhibition of PLK1 has shown limited clinical benefits. We therefore performed a genome-wide synthetic dosage lethality (SDL) screen to identify effective alternative targets and validated over 100 candidates using in vivo and in vitro secondary CRISPR screens. We employed direct-capture Perturb-seq to assess the transcriptional consequences and viability of each SDL perturbation at a single-cell resolution. This revealed IGF2BP2 as a critical genetic dependency that, when targeted, downregulated PLK1 and significantly restricted tumor growth. Mechanistic analyses showed that IGF2BP2 loss disrupted cellular energy metabolism and mitochondrial ATP production by downregulating PLK1 levels as well as genes associated with oxidative phosphorylation. Consistent with this, pharmacological inhibition of IGF2BP2 severely impacts the viability of PLK1-overexpressing cancer cells addicted to higher metabolic rates. Our work offers a novel therapeutic strategy against PLK1-driven heterogeneous malignancies.
Indexed as
Cell Cycle ProteinsNeoplasmsProtein Serine-Threonine KinasesProto-Oncogene ProteinsSynthetic Lethal MutationsAnimalsCell Line, TumorEnergy MetabolismGene Expression Regulation, NeoplasticHumansMicePolo-Like Kinase 1Cell Cycle ProteinsPolo-Like Kinase 1Protein Serine-Threonine KinasesProto-Oncogene Proteinschromosomal instabilityIGF2BP2IMP2in vivo CRISPR screenperturb-seqPLK1single-cell CRISPR screeningsynthetic dosage lethalitytumor heterogeneity
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