The epidermal growth factor receptor (EGFR) is an important target molecule in lung cancer. Now selective EGFR tyrosine kinase inhibitors are in clinical use. Meanwhile, downstream molecules of the EGFR-signal pathway, such as Akt, extracellular signal-regulated kinase (ERK), signal transducer and activator of transcription-3 (STAT3) are under clinical trial.

In this study, combination treatment of gefitinib and inhibitors of Akt (LY294002), ERK (U0126), or STAT3 (STAT3 inhibitor) are examined on lung adenocarcinoma cell lines, NCI-H1650 (gefitinib-sensitive, delE746-750), NCI-H1975 (gefitinib-resistant, L858R/T790M), and NCI-H2347 (gefitinib-resistant, wild-type EGFR). Each inhibitor was combined with gefitinib in a constant ratio, cultured for 72 hours, and analyzed by a modified MTT assay. The median effect method was applied to determine a combination index (CI), where drug synergism was indicated by CI<1, additive effect by CI=1, and antagonism by CI>1. The phosphorylation status of these molecules before and after treatments was determined by ELISA.
 >In NCI-H1650, combination of gefitinib and LY294002 showed stronger synergistic effect with higher concentrations. In NCI-H1975, all combination therapy showed strong synergism. In NCI-H2347, each combination therapy resulted from nearly additive effect to moderate antagonism (Table). Analyses of phosphorylation revealed correlations between the activation patterns of Akt, ERK, and STAT3 and the effects of combination treatment.
 >Together, these data suggest that combination therapy of gefitinib and inhibitors of Akt, ERK, and STAT3 is potentially a practical option for therapy of lung adenocarcinoma. Especially, the addition of these inhibitors to gefitinib would be a novel strategy for gefitinib resistance from the T790M mutation.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA