Dual inhibition of aromatase and epidermal growth factor receptor in non-small cell lung cancer

Abstract

e22189 Background: Recent evidence suggests that estrogen signaling is important in the progression of cancers expressing estrogen receptors (ERs) and may also be involved in the pathogenesis of non-small cell lung cancer (NSCLC). Aromatase is an enzyme complex that catalyses the final step in estrogen synthesis and is present in several tissues, including the lung. In view of a possible functional interaction between the ER and the epidermal growth factor receptor (EGFR) pathways in NSCLC, we investigated the dual inhibition of aromatase and EGFR in NSCLC cell lines. Methods: In the current study we used exemestane, an irreversible steroidal aromatase inactivator, and erlotinib, an EGFR tyrosine kinase inhibitor. The in vitroexperiments were performed using H23 and A549, two NSCLC cell lines with low and high levels of aromatase, respectively. Cell proliferation was measured by MTT assay. Metalloproteinase (MMP) levels were detected by zymography and cell migration was determined by boyden chamber assay. EGFR protein levels detection was performed by immunofluorescense assay. Results: Exemestane and erlotinib inhibited H23 and A549 cell proliferation either alone or in combination, 48 hours after their application. However, the combination of exemestane and erlotinib was more effective than each agent alone, in H23 cells. Furthermore, exemestane decreased MMP-2 and MMP- 9 levels in H23 cells, whereas erlotinib did not. The combination of exemestane and erlotinib had the same effect on MMPs, as exemestane alone. The effect on cell migration was in line with the results in MMPs levels. In A549 cells, no changes in MMPs levels or cell migration were demonstrated. In addition, exemestane altered the location of EGFR protein in H23 cells, but not in A549 cells. Conclusions: Our findings suggest an antiproliferative effect of exemestane and erlotinib in both cell lines, as well as synergy for the combination in H23 cells. The activity of the combination in these cells with low levels of aromatase might involve an additional effect of exemestane on EGFR protein location. Erlotinib did not enhance the effect of exemestane on MMPs secretion and migration in H23 cells. No significant financial relationships to disclose.