ArticleProceedings of the National Academy of Sciences of the United States of America2020
Negative MAPK-ERK regulation sustains CIC-DUX4 oncoprotein expression in undifferentiated sarcoma.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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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
31 citing papers in PubMed, 44 citations in OpenAlex.
- Modeling of Capicua Family Fusion Oncoprotein-Driven Cancers Reveals Gene-Specific Functionality.Molecular cancer research : MCR · 2026Article
- Modeling CIC::DUX4 sarcoma reveals oncogene-mediated MHCI-dependent immune evasion.Molecular cancer · 2025Article
- The CIC::DUX4 oncoprotein maintains DNA integrity through direct regulation of the catalytic subunit of DNA polymerase epsilon (POLE).Oncogene · 2025Article
- Dual-Specificity Protein Phosphatases Targeting Extracellular Signal-Regulated Kinases: Friends or Foes in the Biology of Cancer?International journal of molecular sciences · 2025Review
- Small round cell sarcoma tumoroid biobank reveals CIC::DUX4 sarcoma vulnerability to MCL-1 inhibition.Nature communications · 2025Article
- Upregulation of POLE and proficient DNA repair are features of CIC::DUX4 sarcomas.NPJ precision oncology · 2025Article
- Cancer and benign tumors in myotonic dystrophy, facioscapulohumeral muscular dystrophy, and oculopharyngeal muscular dystrophy: a 23-year, single-center, retrospective study.Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology · 2025Article
- The Capicua C1 Domain Is Required for Full Activity of the CIC::DUX4 Fusion Oncoprotein.Cancer research communications · 2024Article
- Review
- ThebioRxiv : the preprint server for biology · 2024Article
- Biological and therapeutic insights from animal modeling of fusion-driven pediatric soft tissue sarcomas.Disease models & mechanisms · 2024Review
- Article
- Article
- Molecular and therapeutic advancements in Capicua (Frontiers in cell and developmental biology · 2024Review
- Review
- Expression of the CIC-DUX4 fusion oncoprotein mimics human CIC-rearranged sarcoma in genetically engineered mouse models.Research square · 2023Article
- CIC-DUX4 Sarcoma Involving the Skull Base: A Rare Presentation and Review of the Literature.Journal of neurological surgery reports · 2023Article
- Oxidative stress in intervertebral disc degeneration: Molecular mechanisms, pathogenesis and treatment.Cell proliferation · 2023Review
- Article
- TheeLife · 2022Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Transcription factor fusions (TFFs) are present in ∼30% of soft-tissue sarcomas. TFFs are not readily "druggable" in a direct pharmacologic manner and thus have proven difficult to target in the clinic. A prime example is the CIC-DUX4 oncoprotein, which fuses Capicua (CIC) to the double homeobox 4 gene, DUX4. CIC-DUX4 sarcoma is a highly aggressive and lethal subtype of small round cell sarcoma found predominantly in adolescents and young adults. To identify new therapeutic targets in CIC-DUX4 sarcoma, we performed chromatin immunoprecipitation sequencing analysis using patient-derived CIC-DUX4 cells. We uncovered multiple CIC-DUX4 targets that negatively regulate MAPK-ERK signaling. Mechanistically, CIC-DUX4 transcriptionally up-regulates these negative regulators of MAPK to dampen ERK activity, leading to sustained CIC-DUX4 expression. Genetic and pharmacologic MAPK-ERK activation through DUSP6 inhibition leads to CIC-DUX4 degradation and apoptotic induction. Collectively, we reveal a mechanism-based approach to therapeutically degrade the CIC-DUX4 oncoprotein and provide a precision-based strategy to combat this lethal cancer.
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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.