title: InsR/IGF1R Pathway Mediates Resistance to EGFR Inhibitors in Glioblastoma.
abstract: OBJECTIVE
  Aberrant activation of EGFR is a hallmark of glioblastoma. However, EGFR inhibitors exhibit at best modest efficacy in glioblastoma. This is in sharp contrast with the observations in EGFR-mutant lung cancer. We examined whether activation of functionally redundant receptor tyrosine kinases (RTKs) conferred resistance to EGFR inhibitors in glioblastoma.
  
  
  METHODS
  We collected a panel of patient-derived glioblastoma xenograft (PDX) lines that maintained expression of wild-type or mutant EGFR in serial xenotransplantation and tissue cultures. Using this physiologically relevant platform, we tested the abilities of several RTK ligands to protect glioblastoma cells against an EGFR inhibitor, gefitinib. Based on the screening results, we further developed a combination therapy cotargeting EGFR and insulin receptor (InsR)/insulin-like growth factor 1 receptor (IGF1R).
  
  
  RESULTS
  Insulin and IGF1 induced significant protection against gefitinib in the majority of EGFR-dependent PDX lines with one exception that did not express InsR or IGF1R. Blockade of the InsR/IGF1R pathway synergistically improved sensitivity to gefitinib or dacomitinib. Gefitinib alone effectively attenuated EGFR activities and the downstream MEK/ERK pathway. However, repression of AKT and induction of apoptosis required concurrent inhibition of both EGFR and InsR/IGF1R. A combination of gefitinib and OSI-906, a dual InsR/IGF1R inhibitor, was more effective than either agent alone to treat subcutaneous glioblastoma xenograft tumors.
  
  
  CONCLUSIONS
  Our results suggest that activation of the InsR/IGF1R pathway confers resistance to EGFR inhibitors in EGFR-dependent glioblastoma through AKT regulation. Concurrent blockade of these two pathways holds promise to treat EGFR-dependent glioblastoma.
authors.affiliation: Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Yufang
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
authors.forename: Nan
authors.initials: N
authors.lastname: Tang
authors.affiliation: Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Reid C
authors.initials: RC
authors.lastname: Thompson
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Bret C
authors.initials: BC
authors.lastname: Mobley
authors.affiliation: Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Clark
authors.affiliation: Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Jann N
authors.initials: JN
authors.lastname: Sarkaria
authors.affiliation: Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, Tennessee. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee. jialiang.wang@vanderbilt.edu.
authors.forename: Jialiang
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000077156:Gefitinib; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007328:Insulin; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D007334:Insulin-Like Growth Factor I; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D000077156:Gefitinib