Cigarette smoke extract induces EGFR-TKI resistance via promoting EGFR signaling pathway and ROS generation in NSCLC cell lines

- Cigarette smoke extract (CSE) induces EGFR-TKI resistance via EGFR signaling pathway.
- Reactive oxygen species is involved in CSE-induced EGFR-TKI resistance.
- NAC suppresses the activation of EGFR signaling pathway and the increasement of ROS production.
- NAC could reverse the acquired EGFR-TKI resistance induced by CSE in EGFR-mutant and wild-type NSCLC cells.

ObjectivesEpithelial growth factor receptor (EGFR) somatic-mutated non-small cell lung cancer (NSCLC) patients with smoking history always show a poor response to EGFR tyrosine kinase inhibitors (EGFR-TKIs). The aim of the study is to explore the molecular mechanism of EGFR-TKI resistance induced by cigarette smoke extract and investigate the novel anti-resistance strategies.MethodsThe effect of cigarette smoke extract (CSE) on gefitinib sensitivity, EGFR signaling, apoptosis and reactive oxygen species (ROS) levels were detected in vitro by MTT assays, western blot, flow cytometry and laser scanning confocal microscope, respectively.ResultsMTT assays presented that CSE claimed antagonistic effect on gefitinib sensitivity via the up-regulated half maximal inhibitory concentration (IC50) values, western blot showed that CSE instigated EGFR, AKT phosphorylation, while N-Acetyl-l-Cysteine (NAC) could alleviate gefitinib resistance and abort the aberrant phosphorylation in both PC-9 and A549 cells. Confocal microscope and flow cytometry displayed that ROS generation increased after CSE exposure in NSCLC cells and this change could be inhibited by NAC.ConclusionCigarette smoke extract induces EGFR-TKI resistance via promoting EGFR signaling and ROS generation in NSCLC cell lines which could be suppressed by NAC. Alternatively, combined NAC with EGFR-TKIs to treat EGFR mutated NSCLC patients with smoking history may be a potential choice in clinical setting.