Cigarette smoking impairs the response of EGFR-TKIs therapy in lung adenocarcinoma patients by promoting EGFR signaling and epithelial-mesenchymal transition.

Cigarette smoking represents for the highest risk-factor for non-small cell lung cancer (NSCLC), and a growing body of evidence suggested that smoking was associated with a high recurrence and poor therapeutic response of NSCLC as well. On the other hand, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), such as gefitinib, has been proved to be an efficient and safe strategy for treating NSCLC. Although accumulating clinical data suggested that smoking history might influence the therapeutic effects of EGFR-TKIs even in NSCLC patients harboring sensitive EGFR mutation, the exact effects of cigarette smoking on the efficacy of EGFR-TKIs treatment in NSCLC patients remain exclusive. In this study, we firstly identified the adverse effect of smoking exposure on the efficacy of EGFR-TKIs treatment against lung adenocarcinoma in mutation-positive patients by retrospective analysis of clinical data. The hypo-responsiveness of smoking patients on the therapy was accompanied with persistent activation of EGFR-downstream signal molecules ERK1/2 and AKT, which could not be inhibited by gefitinib and thus lead to the failure of EGFR-TKIs treatment. Based on our in vitro data, it was also found that long-term cigarette smoking extract (CSE) exposure induced epithelial-mesenchymal transition (EMT), which might also contribute to acquired resistance to EGFR-TKIs. Taken together, our findings suggested that cigarette smoking negatively regulated the clinical outcome of EGFR-TKIs therapy in lung adenocarcinoma patients, which was correlated with the activation of EGFR signaling and the induction of EMT.