Epidermal growth factor receptor and K-Ras mutations and resistance of lung cancer to insulin-like growth factor 1 receptor tyrosine kinase inhibitors

Authors

  • Woo-Young Kim PhD,

    1. Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
    Current affiliation:
    1. College of Pharmacy, Sookmyung Women's University, Seoul, South Korea
    Search for more papers by this author
  • Ludmila Prudkin PhD,

    1. Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
    Search for more papers by this author
  • Lei Feng MS,

    1. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
    Search for more papers by this author
  • Edward S. Kim MD,

    1. Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
    Search for more papers by this author
  • Bryan Hennessy MD,

    1. Department of Gynecologic Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
    Search for more papers by this author
  • Ju-Seog Lee PhD,

    1. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
    Search for more papers by this author
  • J. Jack Lee PhD,

    1. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
    2. University of Texas Graduate School of Biomedical Sciences, Houston, Texas
    Search for more papers by this author
  • Bonnie Glisson MD,

    1. Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
    Search for more papers by this author
  • Scott M. Lippman MD,

    1. Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
    Search for more papers by this author
  • Ignacio I. Wistuba PhD,

    1. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
    Search for more papers by this author
  • Waun Ki Hong MD,

    1. Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
    Search for more papers by this author
  • Ho-Young Lee PhD

    Corresponding author
    1. Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
    2. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
    • College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea
    Search for more papers by this author

Errata

This article is corrected by:

  1. Errata: Erratum Volume 118, Issue 24, 6301, Article first published online: 17 May 2012

Abstract

BACKGROUND:

Most patients with nonsmall cell lung cancer (NSCLC) have responded poorly to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). The authors investigated the involvement of insulinlike growth factor 1 receptor (IGF-1R) signaling in primary resistance to EGFR TKIs and the molecular determinants of resistance to IGF-1R TKIs.

METHODS:

Phosphorylated IGF-1R/insulin receptor (pIGF-1R/IR) was immunohistochemically evaluated in an NSCLC tissue microarray. The authors analyzed the antitumor effects of an IGF-1R TKI (PQIP or OSI-906), either alone or in combination with a small-molecular inhibitor (PD98059 or U0126) or with siRNA targeting K-Ras or mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK), in vitro and in vivo in NSCLC cells with variable histologic features and EGFR or K-Ras mutations.

RESULTS:

pIGF-1R/IR expression in NSCLC specimens was associated with a history of tobacco smoking, squamous cell carcinoma histology, mutant K-Ras, and wild-type (WT) EGFR, all of which have been strongly associated with poor response to EGFR TKIs. IGF-1R TKIs exhibited significant antitumor activity in NSCLC cells with WT EGFR and WT K-Ras but not in those with mutations in these genes. Introduction of mutant K-Ras attenuated the effects of IGF-1R TKIs on NSCLC cells expressing WT K-Ras. Conversely, inactivation of MEK restored sensitivity to IGF-TKIs in cells carrying mutant K-Ras.

CONCLUSIONS:

The mutation status of both EGFR and K-Ras could be a predictive marker of response to IGF-1R TKIs. Also, MEK antagonism can abrogate primary resistance of NSCLC cells to IGF-1R TKIs. Cancer 2012. © 2012 American Cancer Society.

Ancillary