title: Implication of the insulin-like growth factor-IR pathway in the resistance of non-small cell lung cancer cells to treatment with gefitinib.
abstract: OBJECTIVE
  Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have been found to be effective against lung cancer in vitro, but clinical resistance to these agents has developed as their usage has increased. In this study, we determined whether the insulin-like growth factor I (IGF-I) signaling pathway induces resistance of non-small cell lung cancer (NSCLC) cells to the EGFR tyrosine kinase inhibitor gefitinib.
  
  
  METHODS
  The effects of gefitinib and cetuximab on NSCLC cells, alone or with an IGF-I receptor (IGF-IR) inhibitor, were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, the flow cytometry-based terminal nucleotidyl transferase-mediated nick end labeling assay, coimmunoprecipitation, and Western blot analysis. EGFR and IGFR expression in NSCLC tissues were examined by Western blot analysis.
  
  
  RESULTS
  Gefitinib inhibited NSCLC cell proliferation by inducing apoptosis when IGF-IR signaling was suppressed. Treatment with gefitinib, but not cetuximab, induced EGFR:IGF-IR heterodimerization and activation of IGF-IR and its downstream signaling mediators, resulting in increased survivin expression in NSCLC cell lines with high levels of IGF-IR expression. Inhibition of IGF-IR activation and knockdown of survivin expression led to increased apoptosis. In contrast, overexpression of survivin protected cells with low IGF-IR expression from gefitinib-induced apoptosis. Most NSCLC tissues with EGFR overexpression had associated high levels of IGF-IR expression.
  
  
  CONCLUSIONS
  IGF-IR expression may be useful as a predictive marker for gefitinib treatment of NSCLC. Suppression of IGF-IR signaling pathways may prevent or delay development of gefitinib resistance in patients with NSCLC.
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Floriana
authors.initials: F
authors.lastname: Morgillo
authors.forename: Woo-Young
authors.initials: WY
authors.lastname: Kim
authors.forename: Edward S
authors.initials: ES
authors.lastname: Kim
authors.forename: Fortunato
authors.initials: F
authors.lastname: Ciardiello
authors.forename: Waun Ki
authors.initials: WK
authors.lastname: Hong
authors.forename: Ho-Young
authors.initials: HY
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D045744:Cell Line, Tumor; D019281:Dimerization; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008175:Lung Neoplasms / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000502:physiology; D009363:Neoplasm Proteins / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction; D013002:Somatomedins / Q000378:metabolism*; D000077022:Survivin; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D013002:Somatomedins; D000077022:Survivin; D066246:ErbB Receptors; D000077156:Gefitinib