ArticleJournal of the National Cancer Institute2016
IGF-1R and mTOR Blockade: Novel Resistance Mechanisms and Synergistic Drug Combinations for Ewing Sarcoma.
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Article in Journal of the National Cancer Institute, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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42citing papers in PubMed
3.3field-weighted citation impact, top 8% of its field
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Who cites it
42 citing papers in PubMed, 61 citations in OpenAlex.
- A Practical Compass to Biological Digital Resources and Omics Integration in Ewing Sarcoma.Methods in molecular biology (Clifton, N.J.) · 2027Article
- UBA1 drives cell cycle to promote malignancy and serves as a therapeutic target in Ewing Sarcoma.BMC cancer · 2026Article
- Co-targeting cystathionine gamma-lyase and mTOR: a promising therapeutic strategy in clear cell ovarian cancer.BMC cancer · 2026Article
- Emerging research themes in drug resistance in osteosarcoma: a 25-year bibliometric and visualized analysis.Naunyn-Schmiedeberg's archives of pharmacology · 2026Review
- From 2D to 3D: transforming malignant bone tumor research with advanced culture models.Journal of Zhejiang University. Science. B · 2025Review
- Genetically Modified Mouse Models for Sarcoma Research: A Comprehensive Review.Current oncology reports · 2025Review
- IGF-1R inhibitors in cancer: A review of available evidence and future outlook.Critical reviews in oncology/hematology · 2025Review
- Fusion genes in cancers: Biogenesis, functions, and therapeutic implications.Genes & diseases · 2025Review
- Case Report: Should IGF-1R targeted therapy be revisited in Ewing sarcoma? a report of long-term complete response and review of the literature.Frontiers in oncology · 2025Article
- Clinical research progress of ridaforolimus (AP23573, MK8668) over the past decade: a systemic review.Frontiers in pharmacology · 2024Review
- CRISPR-Cas9 knockout screening identifies KIAA1429 as an essential gene in Ewing sarcoma.Journal of experimental & clinical cancer research : CR · 2023Article
- Review
- Costs and Causes of Oncology Drug Attrition With the Example of Insulin-Like Growth Factor-1 Receptor Inhibitors.JAMA network open · 2023Article
- Role of tumor microenvironment in cancer progression and therapeutic strategy.Cancer medicine · 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
- Latest developments in the pathobiology of Ewing sarcoma.Journal of bone oncology · 2022Review
- The Role of ARID1A in the Nonestrogenic Modulation of IGF-1 Signaling.Molecular cancer research : MCR · 2022Article
- The androgen receptor is a therapeutic target in desmoplastic small round cell sarcoma.Nature communications · 2022Article
- Targeting the IGF/PI3K/mTOR pathway and AXL/YAP1/TAZ pathways in primary bone cancer.Journal of bone oncology · 2022Article
- Metabolic Reprogramming Induces Macrophage Polarization in the Tumor Microenvironment.Frontiers in immunology · 2022Review
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Authors and funding
21 authors at 1 institution in 1 country.
Salah-Eddine Lamhamedi-CherradiDepartments of Sarcoma Medical Oncology (SELC, BAM, VR, RSB, RR, JAL), Hematopathology (DV, HMA), Bioinformatics and Computational Biology (YW, JW), Investigational Cancer Therapeutics (AN, VS), Pediatrics-Patient Care (NCD), Experimental Therapeutics (IF, SS, WP), and Pathology (AJL), The University of Texas MD Anderson Cancer Center, Houston, TX; Departments of Radiology (EMR) and Molecular & Human Genetics (RLM), Baylor College of Medicine, Houston, TX; Department of Pediatric-Oncology, Texas Children's Hospital. Houston, TX (ASB); Departments of Chemical and Biomolecular Engineering and Bioengineering, Rice University, Houston, TX (AGM).
Brian A MenegazDepartments of Sarcoma Medical Oncology (SELC, BAM, VR, RSB, RR, JAL), Hematopathology (DV, HMA), Bioinformatics and Computational Biology (YW, JW), Investigational Cancer Therapeutics (AN, VS), Pediatrics-Patient Care (NCD), Experimental Therapeutics (IF, SS, WP), and Pathology (AJL), The University of Texas MD Anderson Cancer Center, Houston, TX; Departments of Radiology (EMR) and Molecular & Human Genetics (RLM), Baylor College of Medicine, Houston, TX; Department of Pediatric-Oncology, Texas Children's Hospital. Houston, TX (ASB); Departments of Chemical and Biomolecular Engineering and Bioengineering, Rice University, Houston, TX (AGM).
Vandhana RamamoorthyDepartments of Sarcoma Medical Oncology (SELC, BAM, VR, RSB, RR, JAL), Hematopathology (DV, HMA), Bioinformatics and Computational Biology (YW, JW), Investigational Cancer Therapeutics (AN, VS), Pediatrics-Patient Care (NCD), Experimental Therapeutics (IF, SS, WP), and Pathology (AJL), The University of Texas MD Anderson Cancer Center, Houston, TX; Departments of Radiology (EMR) and Molecular & Human Genetics (RLM), Baylor College of Medicine, Houston, TX; Department of Pediatric-Oncology, Texas Children's Hospital. Houston, TX (ASB); Departments of Chemical and Biomolecular Engineering and Bioengineering, Rice University, Houston, TX (AGM).
Deeksha VishwamitraDepartments of Sarcoma Medical Oncology (SELC, BAM, VR, RSB, RR, JAL), Hematopathology (DV, HMA), Bioinformatics and Computational Biology (YW, JW), Investigational Cancer Therapeutics (AN, VS), Pediatrics-Patient Care (NCD), Experimental Therapeutics (IF, SS, WP), and Pathology (AJL), The University of Texas MD Anderson Cancer Center, Houston, TX; Departments of Radiology (EMR) and Molecular & Human Genetics (RLM), Baylor College of Medicine, Houston, TX; Department of Pediatric-Oncology, Texas Children's Hospital. Houston, TX (ASB); Departments of Chemical and Biomolecular Engineering and Bioengineering, Rice University, Houston, TX (AGM).
Ying WangDepartments of Sarcoma Medical Oncology (SELC, BAM, VR, RSB, RR, JAL), Hematopathology (DV, HMA), Bioinformatics and Computational Biology (YW, JW), Investigational Cancer Therapeutics (AN, VS), Pediatrics-Patient Care (NCD), Experimental Therapeutics (IF, SS, WP), and Pathology (AJL), The University of Texas MD Anderson Cancer Center, Houston, TX; Departments of Radiology (EMR) and Molecular & Human Genetics (RLM), Baylor College of Medicine, Houston, TX; Department of Pediatric-Oncology, Texas Children's Hospital. Houston, TX (ASB); Departments of Chemical and Biomolecular Engineering and Bioengineering, Rice University, Houston, TX (AGM).
Rebecca L MaywaldDepartments of Sarcoma Medical Oncology (SELC, BAM, VR, RSB, RR, JAL), Hematopathology (DV, HMA), Bioinformatics and Computational Biology (YW, JW), Investigational Cancer Therapeutics (AN, VS), Pediatrics-Patient Care (NCD), Experimental Therapeutics (IF, SS, WP), and Pathology (AJL), The University of Texas MD Anderson Cancer Center, Houston, TX; Departments of Radiology (EMR) and Molecular & Human Genetics (RLM), Baylor College of Medicine, Houston, TX; Department of Pediatric-Oncology, Texas Children's Hospital. Houston, TX (ASB); Departments of Chemical and Biomolecular Engineering and Bioengineering, Rice University, Houston, TX (AGM).
Adriana S BufordDepartments of Sarcoma Medical Oncology (SELC, BAM, VR, RSB, RR, JAL), Hematopathology (DV, HMA), Bioinformatics and Computational Biology (YW, JW), Investigational Cancer Therapeutics (AN, VS), Pediatrics-Patient Care (NCD), Experimental Therapeutics (IF, SS, WP), and Pathology (AJL), The University of Texas MD Anderson Cancer Center, Houston, TX; Departments of Radiology (EMR) and Molecular & Human Genetics (RLM), Baylor College of Medicine, Houston, TX; Department of Pediatric-Oncology, Texas Children's Hospital. Houston, TX (ASB); Departments of Chemical and Biomolecular Engineering and Bioengineering, Rice University, Houston, TX (AGM).
Izabela FoktDepartments of Sarcoma Medical Oncology (SELC, BAM, VR, RSB, RR, JAL), Hematopathology (DV, HMA), Bioinformatics and Computational Biology (YW, JW), Investigational Cancer Therapeutics (AN, VS), Pediatrics-Patient Care (NCD), Experimental Therapeutics (IF, SS, WP), and Pathology (AJL), The University of Texas MD Anderson Cancer Center, Houston, TX; Departments of Radiology (EMR) and Molecular & Human Genetics (RLM), Baylor College of Medicine, Houston, TX; Department of Pediatric-Oncology, Texas Children's Hospital. Houston, TX (ASB); Departments of Chemical and Biomolecular Engineering and Bioengineering, Rice University, Houston, TX (AGM).
Stanislaw SkoraDepartments of Sarcoma Medical Oncology (SELC, BAM, VR, RSB, RR, JAL), Hematopathology (DV, HMA), Bioinformatics and Computational Biology (YW, JW), Investigational Cancer Therapeutics (AN, VS), Pediatrics-Patient Care (NCD), Experimental Therapeutics (IF, SS, WP), and Pathology (AJL), The University of Texas MD Anderson Cancer Center, Houston, TX; Departments of Radiology (EMR) and Molecular & Human Genetics (RLM), Baylor College of Medicine, Houston, TX; Department of Pediatric-Oncology, Texas Children's Hospital. Houston, TX (ASB); Departments of Chemical and Biomolecular Engineering and Bioengineering, Rice University, Houston, TX (AGM).
Jing WangDepartments of Sarcoma Medical Oncology (SELC, BAM, VR, RSB, RR, JAL), Hematopathology (DV, HMA), Bioinformatics and Computational Biology (YW, JW), Investigational Cancer Therapeutics (AN, VS), Pediatrics-Patient Care (NCD), Experimental Therapeutics (IF, SS, WP), and Pathology (AJL), The University of Texas MD Anderson Cancer Center, Houston, TX; Departments of Radiology (EMR) and Molecular & Human Genetics (RLM), Baylor College of Medicine, Houston, TX; Department of Pediatric-Oncology, Texas Children's Hospital. Houston, TX (ASB); Departments of Chemical and Biomolecular Engineering and Bioengineering, Rice University, Houston, TX (AGM).
Aung NaingDepartments of Sarcoma Medical Oncology (SELC, BAM, VR, RSB, RR, JAL), Hematopathology (DV, HMA), Bioinformatics and Computational Biology (YW, JW), Investigational Cancer Therapeutics (AN, VS), Pediatrics-Patient Care (NCD), Experimental Therapeutics (IF, SS, WP), and Pathology (AJL), The University of Texas MD Anderson Cancer Center, Houston, TX; Departments of Radiology (EMR) and Molecular & Human Genetics (RLM), Baylor College of Medicine, Houston, TX; Department of Pediatric-Oncology, Texas Children's Hospital. Houston, TX (ASB); Departments of Chemical and Biomolecular Engineering and Bioengineering, Rice University, Houston, TX (AGM).
Alexander J LazarDepartments of Sarcoma Medical Oncology (SELC, BAM, VR, RSB, RR, JAL), Hematopathology (DV, HMA), Bioinformatics and Computational Biology (YW, JW), Investigational Cancer Therapeutics (AN, VS), Pediatrics-Patient Care (NCD), Experimental Therapeutics (IF, SS, WP), and Pathology (AJL), The University of Texas MD Anderson Cancer Center, Houston, TX; Departments of Radiology (EMR) and Molecular & Human Genetics (RLM), Baylor College of Medicine, Houston, TX; Department of Pediatric-Oncology, Texas Children's Hospital. Houston, TX (ASB); Departments of Chemical and Biomolecular Engineering and Bioengineering, Rice University, Houston, TX (AGM).
Eric M RohrenDepartments of Sarcoma Medical Oncology (SELC, BAM, VR, RSB, RR, JAL), Hematopathology (DV, HMA), Bioinformatics and Computational Biology (YW, JW), Investigational Cancer Therapeutics (AN, VS), Pediatrics-Patient Care (NCD), Experimental Therapeutics (IF, SS, WP), and Pathology (AJL), The University of Texas MD Anderson Cancer Center, Houston, TX; Departments of Radiology (EMR) and Molecular & Human Genetics (RLM), Baylor College of Medicine, Houston, TX; Department of Pediatric-Oncology, Texas Children's Hospital. Houston, TX (ASB); Departments of Chemical and Biomolecular Engineering and Bioengineering, Rice University, Houston, TX (AGM).
Najat C DawDepartments of Sarcoma Medical Oncology (SELC, BAM, VR, RSB, RR, JAL), Hematopathology (DV, HMA), Bioinformatics and Computational Biology (YW, JW), Investigational Cancer Therapeutics (AN, VS), Pediatrics-Patient Care (NCD), Experimental Therapeutics (IF, SS, WP), and Pathology (AJL), The University of Texas MD Anderson Cancer Center, Houston, TX; Departments of Radiology (EMR) and Molecular & Human Genetics (RLM), Baylor College of Medicine, Houston, TX; Department of Pediatric-Oncology, Texas Children's Hospital. Houston, TX (ASB); Departments of Chemical and Biomolecular Engineering and Bioengineering, Rice University, Houston, TX (AGM).
Vivek SubbiahDepartments of Sarcoma Medical Oncology (SELC, BAM, VR, RSB, RR, JAL), Hematopathology (DV, HMA), Bioinformatics and Computational Biology (YW, JW), Investigational Cancer Therapeutics (AN, VS), Pediatrics-Patient Care (NCD), Experimental Therapeutics (IF, SS, WP), and Pathology (AJL), The University of Texas MD Anderson Cancer Center, Houston, TX; Departments of Radiology (EMR) and Molecular & Human Genetics (RLM), Baylor College of Medicine, Houston, TX; Department of Pediatric-Oncology, Texas Children's Hospital. Houston, TX (ASB); Departments of Chemical and Biomolecular Engineering and Bioengineering, Rice University, Houston, TX (AGM).
Robert S BenjaminDepartments of Sarcoma Medical Oncology (SELC, BAM, VR, RSB, RR, JAL), Hematopathology (DV, HMA), Bioinformatics and Computational Biology (YW, JW), Investigational Cancer Therapeutics (AN, VS), Pediatrics-Patient Care (NCD), Experimental Therapeutics (IF, SS, WP), and Pathology (AJL), The University of Texas MD Anderson Cancer Center, Houston, TX; Departments of Radiology (EMR) and Molecular & Human Genetics (RLM), Baylor College of Medicine, Houston, TX; Department of Pediatric-Oncology, Texas Children's Hospital. Houston, TX (ASB); Departments of Chemical and Biomolecular Engineering and Bioengineering, Rice University, Houston, TX (AGM).
Ravin RatanDepartments of Sarcoma Medical Oncology (SELC, BAM, VR, RSB, RR, JAL), Hematopathology (DV, HMA), Bioinformatics and Computational Biology (YW, JW), Investigational Cancer Therapeutics (AN, VS), Pediatrics-Patient Care (NCD), Experimental Therapeutics (IF, SS, WP), and Pathology (AJL), The University of Texas MD Anderson Cancer Center, Houston, TX; Departments of Radiology (EMR) and Molecular & Human Genetics (RLM), Baylor College of Medicine, Houston, TX; Department of Pediatric-Oncology, Texas Children's Hospital. Houston, TX (ASB); Departments of Chemical and Biomolecular Engineering and Bioengineering, Rice University, Houston, TX (AGM).
Waldemar PriebeDepartments of Sarcoma Medical Oncology (SELC, BAM, VR, RSB, RR, JAL), Hematopathology (DV, HMA), Bioinformatics and Computational Biology (YW, JW), Investigational Cancer Therapeutics (AN, VS), Pediatrics-Patient Care (NCD), Experimental Therapeutics (IF, SS, WP), and Pathology (AJL), The University of Texas MD Anderson Cancer Center, Houston, TX; Departments of Radiology (EMR) and Molecular & Human Genetics (RLM), Baylor College of Medicine, Houston, TX; Department of Pediatric-Oncology, Texas Children's Hospital. Houston, TX (ASB); Departments of Chemical and Biomolecular Engineering and Bioengineering, Rice University, Houston, TX (AGM).
Antonios G MikosDepartments of Sarcoma Medical Oncology (SELC, BAM, VR, RSB, RR, JAL), Hematopathology (DV, HMA), Bioinformatics and Computational Biology (YW, JW), Investigational Cancer Therapeutics (AN, VS), Pediatrics-Patient Care (NCD), Experimental Therapeutics (IF, SS, WP), and Pathology (AJL), The University of Texas MD Anderson Cancer Center, Houston, TX; Departments of Radiology (EMR) and Molecular & Human Genetics (RLM), Baylor College of Medicine, Houston, TX; Department of Pediatric-Oncology, Texas Children's Hospital. Houston, TX (ASB); Departments of Chemical and Biomolecular Engineering and Bioengineering, Rice University, Houston, TX (AGM).
Hesham M AminDepartments of Sarcoma Medical Oncology (SELC, BAM, VR, RSB, RR, JAL), Hematopathology (DV, HMA), Bioinformatics and Computational Biology (YW, JW), Investigational Cancer Therapeutics (AN, VS), Pediatrics-Patient Care (NCD), Experimental Therapeutics (IF, SS, WP), and Pathology (AJL), The University of Texas MD Anderson Cancer Center, Houston, TX; Departments of Radiology (EMR) and Molecular & Human Genetics (RLM), Baylor College of Medicine, Houston, TX; Department of Pediatric-Oncology, Texas Children's Hospital. Houston, TX (ASB); Departments of Chemical and Biomolecular Engineering and Bioengineering, Rice University, Houston, TX (AGM).
Joseph A LudwigDepartments of Sarcoma Medical Oncology (SELC, BAM, VR, RSB, RR, JAL), Hematopathology (DV, HMA), Bioinformatics and Computational Biology (YW, JW), Investigational Cancer Therapeutics (AN, VS), Pediatrics-Patient Care (NCD), Experimental Therapeutics (IF, SS, WP), and Pathology (AJL), The University of Texas MD Anderson Cancer Center, Houston, TX; Departments of Radiology (EMR) and Molecular & Human Genetics (RLM), Baylor College of Medicine, Houston, TX; Department of Pediatric-Oncology, Texas Children's Hospital. Houston, TX (ASB); Departments of Chemical and Biomolecular Engineering and Bioengineering, Rice University, Houston, TX (AGM) jaludwig@mdanderson.org.
The University of Texas MD Anderson Cancer Center · US
Funding
Tumor Evolution and Metastasis ProgramP30CA016672 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI Scott Kopetz · 1985 to 2026
$290.8MRole of IGF-IR tyrosine kinase in NPM-ALK-expressing T-cell lymphomaR01CA151533 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI AMIN, HESHAM M · 2011 to 2015
$1.6MNCI NIH HHS P30 CA016672NCI NIH HHS R01 CA151533
Abstract
backgroundTherapies cotargeting insulin-like growth factor receptor 1 (IGF-1R) and mammalian target of rapamycin (mTOR) have demonstrated remarkable, albeit short-lived, clinical responses in a subset of Ewing sarcoma (ES) patients. However, the mechanisms of resistance and applicable strategies for overcoming drug resistance to the IGF-1R/mTOR blockade are still undefined.
methodsTo elucidate predominant mechanism(s) of acquired drug resistance while identifying synergistic drug combinations that improve clinical efficacy, we generated more than 18 ES cell lines resistant to IGF-1R- or mTOR-targeted therapy. Two small-molecule inhibitors of IGF-1R were chosen, NVP-ADW-742 (IGF-1R-selective) and OSI-906 (a dual IGF-1R/insulin receptor alpha [IR-α] inhibitor). Reverse-phase protein lysate arrays (RPPAs) revealed proteomic changes linked to IGF-1R/mTOR resistance, and selected proteins were validated in cell-based assays, xenografts, and within human clinical samples. All statistical tests were two-sided.
resultsNovel mechanisms of resistance (MOR) emerged after dalotuzumab-, NVP-ADW-742-, and OSI-906-based targeting of IGF-1R. MOR to dalotuzumab included upregulation of IRS1, PI3K, and STAT3, as well as p38 MAPK, which was also induced by OSI-906. pEIF4E(Ser209), a key regulator of Cap-dependent translation, was induced in ridaforolimus-resistant ES cell lines. Unique drug combinations targeting IGF-1R and PI3K-alpha or Mnk and mTOR were synergistic in vivo and vitro (P < .001) as assessed respectively by Mantel-Cox and isobologram testing.
conclusionsWe discovered new druggable targets expressed by chemoresistant ES cells, xenografts, and relapsed human tumors. Joint suppression of these newfound targets, in concert with IGF-1R or mTOR blockade, should improve clinical outcomes.
Indexed as
Adenosine TriphosphatasesAnimalsAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedAntineoplastic Combined Chemotherapy ProtocolsBone NeoplasmsCation Transport ProteinsCell Line, TumorCopper-Transporting ATPasesDrug Resistance, NeoplasmDrug SynergismHumansImidazolesInsulin Receptor Substrate ProteinsMaleMice3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanolAdenosine TriphosphatasesAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedATP7A protein, humanCation Transport ProteinsCopper-Transporting ATPasesdalotuzumabEIF4ENIF1 protein, humanIGF1R protein, humanImidazolesInsulin Receptor Substrate ProteinsIRS1 protein, humanMTOR protein, humanNucleocytoplasmic Transport ProteinsNVP ADW742p38 Mitogen-Activated Protein KinasesPhosphatidylinositol 3-KinasePhosphoinositide-3 Kinase InhibitorsPyrazinesPyrimidinesPyrrolesReceptor, IGF Type 1Receptors, SomatomedinridaforolimusSirolimusSTAT3 Transcription FactorTOR Serine-Threonine Kinases
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