High level of AKT activity is associated with resistance to MEK inhibitor AZD6244 (ARRY-142886)

Jieru Meng, Henry Peng, Bingbing Dai, Wei Guo, Li Wang, Lin Ji, John D. Minna, Christine M. Chresta, Paul D. Smith, Bingliang Fang, Jack A. Roth

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

MEK/ERK activities are increased in many primary lung cancers, and MEK inhibitors have been tested clinically for treatment of non-small cell lung cancers. The molecular mechanisms of resistance to MEK inhibitors have not been clearly demonstrated, however, and no molecular biomarker that can predict lung cancer response to MEK inhibitors is available. By determining the dose-responses of 35 human lung cancer cell lines to MEK-specific inhibitor AZD6244, we identified subsets of lung cancer cell lines that are either sensitive or resistant to this agent. Subsequent molecular characterization showed that treatment with AZD6244 suppressed ERK phosphorylation in both sensitive and resistant cells, suggesting that resistance is not mediated by the activities of MEK/ERK themselves. Interestingly, we found that levels of phosphorylated AKT were dramatically higher in the resistant cancer cells than in the sensitive cells. Stable transfection of dominant-negative AKT into resistant cells by retroviral infection restored their susceptibility to AZD6244. These results indicate that phosphorylated AKT may be a biomarker of response to AZD6244 and that modulation of AKT activity may be a useful approach to overcome resistance to MEK inhibitors.

Original languageEnglish (US)
Pages (from-to)2073-2080
Number of pages8
JournalCancer Biology and Therapy
Volume8
Issue number21
DOIs
StatePublished - Nov 1 2009

Keywords

  • AKT
  • AZD6244
  • Lung cancer
  • MEK inhibitor
  • Resistance

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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    Meng, J., Peng, H., Dai, B., Guo, W., Wang, L., Ji, L., Minna, J. D., Chresta, C. M., Smith, P. D., Fang, B., & Roth, J. A. (2009). High level of AKT activity is associated with resistance to MEK inhibitor AZD6244 (ARRY-142886). Cancer Biology and Therapy, 8(21), 2073-2080. https://doi.org/10.4161/cbt.8.21.9844