Epidermal growth factor receptor and K-Ras mutations and resistance of lung cancer to insulin-like growth factor 1 receptor tyrosine kinase inhibitors
Version of Record online: 22 FEB 2012
Copyright © 2012 American Cancer Society
Volume 118, Issue 16, pages 3993–4003, 15 August 2012
How to Cite
Kim, W.-Y., Prudkin, L., Feng, L., Kim, E. S., Hennessy, B., Lee, J.-S., Lee, J. J., Glisson, B., Lippman, S. M., Wistuba, I. I., Hong, W. K. and Lee, H.-Y. (2012), Epidermal growth factor receptor and K-Ras mutations and resistance of lung cancer to insulin-like growth factor 1 receptor tyrosine kinase inhibitors. Cancer, 118: 3993–4003. doi: 10.1002/cncr.26656
- Issue online: 3 AUG 2012
- Version of Record online: 22 FEB 2012
- Manuscript Revised: 2 SEP 2011
- Manuscript Accepted: 2 SEP 2011
- Manuscript Received: 24 JUN 2011
Vol. 118, Issue 24, 6301, Version of Record online: 17 MAY 2012
- epidermal growth factor receptor;
- insulinlike growth factor 1 receptor;
- lung cancer;
- tyrosine kinase inhibitors
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.
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.
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.
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.