ArticleMolecular cancer therapeutics2019
Targeting the IGF1R/PI3K/AKT Pathway Sensitizes Ewing Sarcoma to BET Bromodomain Inhibitors.
Article in Molecular cancer therapeutics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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The trial behind it
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
24 citing papers in PubMed, 39 citations in OpenAlex.
- Targeted and molecular therapies in Ewing sarcoma: a comprehensive review of preclinical and clinical advances.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- Mechanisms of hesperetin in alleviating diabetic nephropathy: Network pharmacology, molecular docking, and experimental validation.Journal of diabetes investigation · 2026Article
- Therapeutic Targeting of BET Proteins in Sarcoma.Molecular cancer therapeutics · 2025Review
- Functional combinatorial precision medicine for predicting and optimizing soft tissue sarcoma treatments.NPJ precision oncology · 2025Article
- CDK4/6 and BET inhibitors synergistically suppress pancreatic tumor growth and epithelial-to-mesenchymal transition by regulating the GSK3β-mediated Wnt/β-catenin pathway.Cancer drug resistance (Alhambra, Calif.) · 2025Article
- Xenografting Human Musculoskeletal Sarcomas in Mice, Chick Embryo, and Zebrafish: How to Boost Translational Research.Biomedicines · 2024Review
- Super-enhancers and the super-enhancer reader BRD4: tumorigenic factors and therapeutic targets.Cell death discovery · 2023Review
- BET in hematologic tumors: Immunity, pathogenesis, clinical trials and drug combinations.Genes & diseases · 2023Review
- EWS/FLI1 Characterization, Activation, Repression, Target Genes and Therapeutic Opportunities in Ewing Sarcoma.International journal of molecular sciences · 2023Review
- Redundant Signaling as the Predominant Mechanism for Resistance to Antibodies Targeting the Type-I Insulin-Like Growth Factor Receptor in Cells Derived from Childhood Sarcoma.Molecular cancer therapeutics · 2023Article
- Integration of signaling pathway and bromodomain and extra-terminal domain inhibition for the treatment of mutant Kirsten rat sarcoma viral oncogene homolog cancer.Exploration of targeted anti-tumor therapy · 2023Review
- CircRASSF2 promotes IGF1R and osteosarcoma metastasis via sponging miR-6838-5p.Annals of translational medicine · 2022Article
- High enhancer activity is an epigenetic feature of HPV negative atypical head and neck squamous cell carcinoma.Frontiers in cell and developmental biology · 2022Article
- Review
- Achieving clinical success with BET inhibitors as anti-cancer agents.British journal of cancer · 2021Review
- Novel Regulators of the IGF System in Cancer.Biomolecules · 2021Review
- Insulin-like growth factor receptor signaling in tumorigenesis and drug resistance: a challenge for cancer therapy.Journal of hematology & oncology · 2020Review
- The Role of Tyrosine Kinases as a Critical Prognostic Parameter and Its Targeted Therapies in Ewing Sarcoma.Frontiers in cell and developmental biology · 2020Review
- IL-10 induces MC3T3-E1 cells differentiation towards osteoblastic fate in murine model.Journal of cellular and molecular medicine · 2020Article
- Targeting the undruggable: exploiting neomorphic features of fusion oncoproteins in childhood sarcomas for innovative therapies.Cancer metastasis reviews · 2019Review
Corrections and comments
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Authors and funding
5 authors at 5 institutions in 2 countries.
Funding
Abstract
Inhibitors of the bromodomain and extra-terminal domain (BET) family proteins modulate EWS-FLI1 activities in Ewing sarcoma. However, the efficacy of BET inhibitors as a monotherapy was moderate and transient in preclinical models. The objective of this study was to identify the mechanisms mediating intrinsic resistance to BET inhibitors and develop more effective combination treatments for Ewing sarcoma. Using a panel of Ewing sarcoma cell lines and patient-derived xenograft lines (PDX), we demonstrated that IGF1R inhibitors synergistically increased sensitivities to BET inhibitors and induced potent apoptosis when combined with BET inhibitors. Constitutively activated AKT significantly protected Ewing sarcoma cells against BET inhibitors, suggesting that IGF1R regulates responsiveness to BET inhibitors mainly through the PI3K/AKT pathway. Although two Ewing sarcoma cell lines were resistant to IGF1R inhibitors, they retained synergistic response to a combination of BET inhibitors and mTOR inhibitors, suggesting that BET proteins, when IGF1R is not functional, cross-talk with its downstream molecules. Furthermore, the combination of a BET inhibitor and an IGF1R inhibitor induced potent and durable response in xenograft tumors, whereas either agent alone was less effective. Taken together, our results suggest that IGF1R and the downstream PI3K/AKT/mTOR kinase cascade mediate intrinsic resistance to BET inhibitors in Ewing sarcoma. These results provide the proof-of-concept for combining BET inhibitors with agents targeting the IGF1R pathway for treating advanced Ewing sarcoma.
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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.