The Ras/Raf/MEK/ERK signaling pathway plays important role in tumorigenesis and in maintenance of malignant phenotype. As the major executive molecules in this pathway, MEK/ERK have been found highly active in many primary lung cancers. More recently, 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 resistance to AZD6244 and that modulation of AKT activity may be a useful approach to overcome resistance to MEK inhibitors.
Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3699.
100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO