title: Insulin-like growth factor-1 receptor (IGF-1R) as a biomarker for resistance to the tyrosine kinase inhibitor gefitinib in non-small cell lung cancer.
abstract: BACKGROUND
  The insulin-like growth factor-1 receptor (IGF-1R) pathway is known to play a role in the acquisition of resistance to epidermal growth factor receptor (EGFR)-specific tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). However, its exact role in TKI resistance has so far remained unclear. Here, we interrogated the hypothesis that the IGF-1R may serve as a biomarker for, and may play a role in, intrinsic resistance to the EGFR-specific TKI gefitinib in NSCLC.
  
  
  METHODS
  Total-IGF-1R and phosphorylated (p)-IGF-1R expression levels were related to gefitinib sensitivity in 23 NSCLC cell lines. This sensitivity was re-evaluated after knocking down IGF-1R expression and after IGF-1R up-regulation through exogenous IGF-1 expression. The utility of IGF-1R expression as a predictive biomarker was also evaluated by immunohistochemistry (IHC) in 98 primary NSCLC samples from patients treated with gefitinib.
  
  
  RESULTS
  Seventeen of the cell lines tested were resistant to gefitinib, whereas 3 cell lines were sensitive. The three remaining cell lines showed intermediate values. Thirteen resistant cell lines were found to be positive for total-IGF-1R expression, while all the sensitive cell lines were negative, resulting in a positive predictive value (PPV) of 81% for total-IGF-1R to predict resistance. Seven resistant cell lines exhibited high p-IGF-1R levels, whereas all 3 sensitive cell lines were negative for p-IGF-1R, resulting in a PPV of 100% for p-IGF-1R to predict resistance. Neither a knock-down of IGF-1R expression nor an activation of the IGF1-R pathway through exogenous IGF-1 expression affected gefitinib sensitivity. In primary NSCLC tissues, IGF-1R expression was found to be significantly higher in patients with progressive disease, i.e., showing gefitinib resistance, as compared to those with a complete or partial response.
  
  
  CONCLUSIONS
  IGF-1R acts as a predictor for resistance to gefitinib in NSCLC cell lines and NSCLC patients, but does not seem to play a role in the intrinsic resistance to this drug. High total-IGF-1R and p-IGR-1R levels may predict such a resistance. Since the underlying mechanism does not appear to be related to proliferation induction, alternative pathways should be explored.
authors.affiliation: Department of Medicine/Medical Oncology, University of Colorado Cancer Center, UC Denver, 12801 E 17th Ave, Mail Stop 8177, Aurora, CO 80045, USA. nirp@post.tau.ac.il
authors.forename: Nir
authors.initials: N
authors.lastname: Peled
authors.forename: Murry W
authors.initials: MW
authors.lastname: Wynes
authors.forename: Norihiko
authors.initials: N
authors.lastname: Ikeda
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Ohira
authors.forename: Koichi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Jin
authors.initials: J
authors.lastname: Qian
authors.forename: Maya
authors.initials: M
authors.lastname: Ilouze
authors.forename: Ronen
authors.initials: R
authors.lastname: Brenner
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kato
authors.forename: Celine
authors.initials: C
authors.lastname: Mascaux
authors.forename: Fred R
authors.initials: FR
authors.lastname: Hirsch
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D020128:Inhibitory Concentration 50; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D034622:RNA Interference; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; D000077156:Gefitinib