ArticleCancer letters2017
The small molecule inhibitor YK-4-279 disrupts mitotic progression of neuroblastoma cells, overcomes drug resistance and synergizes with inhibitors of mitosis.
Article in Cancer letters, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 40 citations in OpenAlex.
- Switching off CK2-mediated activation of survivin offers new therapeutic opportunities in neuroblastoma.Experimental & molecular medicine · 2026Article
- BRAF-induced EHF Expression Affects TERT in Aggressive Papillary Thyroid Cancer.The Journal of clinical endocrinology and metabolism · 2025Article
- YK-4-279 Induces Osteosarcoma Cell Cycle Arrest, DNA Damage Response, and Apoptosis by Regulating the MAPK Cascade.Drug design, development and therapy · 2025Article
- Xanthohumol overcomes osimertinib resistance via governing ubiquitination-modulated Ets-1 turnover.Cell death discovery · 2024Article
- Catalytic Asymmetric Difluoroalkylation Using In Situ Generated Difluoroenol Species as the Privileged Synthon.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- The DNA/RNA helicase DHX9 orchestrates the KDM2B-mediated transcriptional regulation of YAP1 in Ewing sarcoma.Oncogene · 2024Article
- Article
- Refined high-content imaging-based phenotypic drug screening in zebrafish xenografts.NPJ precision oncology · 2023Review
- TK216 targets microtubules in Ewing sarcoma cells.Cell chemical biology · 2022Article
- The DNA/RNA helicase DHX9 contributes to the transcriptional program of the androgen receptor in prostate cancer.Journal of experimental & clinical cancer research : CR · 2022Article
- YK-4-279 Attenuates Progression of Pre-Existing Pigmented Lesions to Nodular Melanoma in a Mouse Model.Cancers · 2021Article
- Synthetic Heterocyclic Derivatives as Kinase Inhibitors Tested for the Treatment of Neuroblastoma.Molecules (Basel, Switzerland) · 2021Review
- Targeting Pan-ETS Factors Inhibits Melanoma Progression.Cancer research · 2021Article
- Down-Regulating HAUS6 Suppresses Cell Proliferation by Activating the p53/p21 Pathway in Colorectal Cancer.Frontiers in cell and developmental biology · 2021Article
- Upfront Treatment of Pediatric High-Risk Neuroblastoma With Chemotherapy, Surgery, and Radiotherapy Combination: The CCCG-NB-2014 Protocol.Frontiers in oncology · 2021Article
- The ETS Inhibitor YK-4-279 Suppresses Thyroid Cancer Progression Independent ofFrontiers in oncology · 2021Article
- p53 Loss Mediates Hypersensitivity to ETS Transcription Factor Inhibition Based on PARylation-Mediated Cell Death Induction.Cancers · 2020Article
- Development of an Ewing sarcoma cell line with resistance to EWS‑FLI1 inhibitor YK‑4‑279.Molecular medicine reports · 2020Article
- Function and regulation of the PEA3 subfamily of ETS transcription factors in cancer.American journal of cancer research · 2020Review
- Article
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
Abstract
Neuroblastoma is a biologically and clinically heterogeneous pediatric malignancy that includes a high-risk subset for which new therapeutic agents are urgently required. As well as MYCN amplification, activating point mutations of ALK and NRAS are associated with high-risk and relapsing neuroblastoma. As both ALK and RAS signal through the MEK/ERK pathway, we sought to evaluate two previously reported inhibitors of ETS-related transcription factors, which are transcriptional mediators of the Ras-MEK/ERK pathway in other cancers. Here we show that YK-4-279 suppressed growth and triggered apoptosis in nine neuroblastoma cell lines, while BRD32048, another ETV1 inhibitor, was ineffective. These results suggest that YK-4-279 acts independently of ETS-related transcription factors. Further analysis reveals that YK-4-279 induces mitotic arrest in prometaphase, resulting in subsequent cell death. Mechanistically, we show that YK-4-279 inhibits the formation of kinetochore microtubules, with treated cells showing a broad range of abnormalities including multipolar, fragmented and unseparated spindles, together leading to disrupted progression through mitosis. Notably, YK-4-279 does not affect microtubule acetylation, unlike the conventional mitotic poisons paclitaxel and vincristine. Consistent with this, we demonstrate that YK-4-279 overcomes vincristine-induced resistance in two neuroblastoma cell-line models. Furthermore, combinations of YK-4-279 with vincristine, paclitaxel or the Aurora kinase A inhibitor MLN8237/Alisertib show strong synergy, particularly at low doses. Thus, YK-4-279 could potentially be used as a single-agent or in combination therapies for the treatment of high-risk and relapsing neuroblastoma, as well as other cancers.
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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.