title: IGF-1R and mTOR Blockade: Novel Resistance Mechanisms and Synergistic Drug Combinations for Ewing Sarcoma.
abstract: Therapies 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.
  
  
  
  To 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.
  
  
  
  Novel 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.
  
  
  
  We 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.
authors: Departments 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).
authors: Salah-Eddine
authors: SE
authors: Lamhamedi-Cherradi
authors: Departments 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).
authors: Brian A
authors: BA
authors: Menegaz
authors: Departments 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).
authors: Vandhana
authors: V
authors: Ramamoorthy
authors: Departments 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).
authors: Deeksha
authors: D
authors: Vishwamitra
authors: Departments 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).
authors: Ying
authors: Y
authors: Wang
authors: Departments 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).
authors: Rebecca L
authors: RL
authors: Maywald
authors: Departments 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).
authors: Adriana S
authors: AS
authors: Buford
authors: Departments 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).
authors: Izabela
authors: I
authors: Fokt
authors: Departments 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).
authors: Stanislaw
authors: S
authors: Skora
authors: Departments 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).
authors: Jing
authors: J
authors: Wang
authors: Departments 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).
authors: Aung
authors: A
authors: Naing
authors: Departments 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).
authors: Alexander J
authors: AJ
authors: Lazar
authors: Departments 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).
authors: Eric M
authors: EM
authors: Rohren
authors: Departments 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).
authors: Najat C
authors: NC
authors: Daw
authors: Departments 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).
authors: Vivek
authors: V
authors: Subbiah
authors: Departments 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).
authors: Robert S
authors: RS
authors: Benjamin
authors: Departments 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).
authors: Ravin
authors: R
authors: Ratan
authors: Departments 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).
authors: Waldemar
authors: W
authors: Priebe
authors: Departments 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).
authors: Antonios G
authors: AG
authors: Mikos
authors: Departments 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).
authors: Hesham M
authors: HM
authors: Amin
authors: Departments 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.
authors: Joseph A
authors: JA
authors: Ludwig
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D000073840:Copper-Transporting ATPases; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D029543:Nucleocytoplasmic Transport Proteins / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D040081:Protein Array Analysis; D011719:Pyrazines / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D011758:Pyrroles / Q000008:administration & dosage; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000378:metabolism*; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D027682:Cation Transport Proteins; C411571:EIF4ENIF1 protein, human; C000597236:IGF1R protein, human; C526292:IRS1 protein, human; D007093:Imidazoles; D055504:Insulin Receptor Substrate Proteins; D029543:Nucleocytoplasmic Transport Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011719:Pyrazines; D011743:Pyrimidines; D011758:Pyrroles; D017451:Receptors, Somatomedin; D050796:STAT3 Transcription Factor; C515074:ridaforolimus; C569480:dalotuzumab; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D017526:Receptor, IGF Type 1; D058570:TOR Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases; C502355:NVP ADW742; D020123:Sirolimus