Cellular Oncology

, Volume 36, Issue 4, pp 277–288

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

  • Nir Peled
  • Murry W. Wynes
  • Norihiko Ikeda
  • Tatsuo Ohira
  • Koichi Yoshida
  • Jin Qian
  • Maya Ilouze
  • Ronen Brenner
  • Yasufumi Kato
  • Celine Mascaux
  • Fred R. Hirsch
Original Paper

DOI: 10.1007/s13402-013-0133-9

Cite this article as:
Peled, N., Wynes, M.W., Ikeda, N. et al. Cell Oncol. (2013) 36: 277. doi:10.1007/s13402-013-0133-9

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.

Keywords

NSCLC EGFR IGF-1R Therapy resistance Biomarkers 

Copyright information

© International Society for Cellular Oncology 2013

Authors and Affiliations

  • Nir Peled
    • 1
    • 2
    • 3
  • Murry W. Wynes
    • 1
  • Norihiko Ikeda
    • 4
  • Tatsuo Ohira
    • 4
  • Koichi Yoshida
    • 4
  • Jin Qian
    • 1
  • Maya Ilouze
    • 2
    • 3
  • Ronen Brenner
    • 2
    • 3
  • Yasufumi Kato
    • 1
  • Celine Mascaux
    • 1
  • Fred R. Hirsch
    • 1
  1. 1.Departments of Medicine/Medical Oncology and PathologyUniversity of Colorado Cancer Center, UC DenverAuroraUSA
  2. 2.The Thoracic Research and Detection CenterSheba Medical CenterTel HashomerIsrael
  3. 3.Tel-Aviv UniversityTel-AvivIsrael
  4. 4.Department of SurgeryTokyo Medical UniversityTokyoJapan