ArticleCell death and differentiation2015
Identification of synthetic lethality of PLK1 inhibition and microtubule-destabilizing drugs.
Article in Cell death and differentiation, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 57 citations in OpenAlex.
- PLK1 inhibition enhances Brentuximab vedotin efficacy in CD30-positive T-cell lymphoma via spindle assembly checkpoint activation.Leukemia · 2026Article
- GEF-H1 upon microtubule destabilization drives ZBP1-dependent necroptosis.Cell death and differentiation · 2026Article
- Expanding Synthetic Lethality in DNA Damage Response-Defective Cancers Through Stress Phenotype-Guided Kinase Targeting.International journal of molecular sciences · 2026Review
- C1orf226 Promotes Glioma Stemness and Oncogenesis in Glioma via PLK1-Mediated Wnt/β-Catenin Signaling.Cancer medicine · 2026Article
- Artificial cell vesicle-mediated delivery ofFrontiers in bioengineering and biotechnology · 2025Article
- Advances in Synthetic Lethality in Potential Oncology Therapeutic Approaches.Current topics in medicinal chemistry · 2025Review
- BRCA1 orchestrates the response to BI-2536 and its combination with alisertib in MYC-driven small cell lung cancer.Cell death & disease · 2024Article
- Rhabdomyosarcoma: Current Therapy, Challenges, and Future Approaches to Treatment Strategies.Cancers · 2023Review
- Co-targeting MCL-1 and ERK1/2 kinase induces mitochondrial apoptosis in rhabdomyosarcoma cells.Translational oncology · 2022Article
- Onvansertib and paclitaxel combined in platinum-resistant ovarian carcinomas.Therapeutic advances in medical oncology · 2022Article
- Identification of small molecules that mitigate vincristine-induced neurotoxicity while sensitizing leukemia cells to vincristine.Clinical and translational science · 2021Article
- A Cereblon Modulator CC-885 Induces CRBN- and p97-Dependent PLK1 Degradation and Synergizes with Volasertib to Suppress Lung Cancer.Molecular therapy oncolytics · 2020Article
- Co-inhibition of BET proteins and PI3Kα triggers mitochondrial apoptosis in rhabdomyosarcoma cells.Oncogene · 2020Article
- Article
- Cell cycle arrest in mitosis promotes interferon-induced necroptosis.Cell death and differentiation · 2019Article
- A requirement of Polo-like kinase 1 in murine embryonic myogenesis and adult muscle regeneration.eLife · 2019Article
- VISAGE Reveals a Targetable Mitotic Spindle Vulnerability in Cancer Cells.Cell systems · 2019Article
- Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy.Medicinal research reviews · 2019Review
- Identification of Rigosertib for the Treatment of Recessive Dystrophic Epidermolysis Bullosa-Associated Squamous Cell Carcinoma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2019Article
- Evolutionary design principles in metabolism.Proceedings. Biological sciences · 2019Review
Corrections and comments
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Authors and funding
3 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Polo-like kinase 1 (PLK1) is frequently overexpressed in cancer, which correlates with poor prognosis. Therefore, we investigated PLK1 as therapeutic target using rhabdomyosarcoma (RMS) as a model. Here, we identify a novel synthetic lethal interaction of PLK1 inhibitors and microtubule-destabilizing drugs in preclinical RMS models and elucidate the underlying molecular mechanisms of this synergism. PLK1 inhibitors (i.e., BI 2536 and BI 6727) synergistically induce apoptosis together with microtubule-destabilizing drugs (i.e., vincristine (VCR), vinblastine (VBL) and vinorelbine (VNR)) in several RMS cell lines (combination index <0.9) including a patient-derived primary RMS culture. Importantly, PLK1 inhibitors and VCR cooperate to significantly suppress RMS growth in two in vivo models, including a mouse xenograft model, without causing additive toxicity. In addition, no toxicity was observed in non-malignant fibroblast or myoblast cultures. Mechanistically, BI 2536/VCR co-treatment triggers mitotic arrest, which initiates mitochondrial apoptosis by inactivation of antiapoptotic BCL-2 family proteins, followed by BAX/BAK activation, production of reactive oxygen species (ROS) and activation of caspase-dependent or caspase-independent effector pathways. This conclusion is supported by data showing that BI 2536/VCR-induced apoptosis is significantly inhibited by preventing cells to enter mitosis, by overexpression of BCL-2 or a non-degradable MCL-1 mutant, by BAK knockdown, ROS scavengers, caspase inhibition or endonuclease G silencing. This identification of a novel synthetic lethality of PLK1 inhibitors and microtubule-destabilizing drugs has important implications for developing PLK1 inhibitor-based combination treatments.
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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.