Cigarette smoke-induced LKB1/AMPK pathway deficiency reduces EGFR TKI sensitivity in NSCLC

Smoker patients with non-small cell lung cancer (NSCLC) have poorer prognosis and survival than those without smoking history. However, the mechanisms underlying the low response rate of those patients to EGFR tyrosine kinase inhibitors (TKIs) are not well understood. Here we report that exposure to cigarette smoke extract enhances glycolysis and attenuates AMP-activated protein kinase (AMPK)-dependent inhibition of mTOR; this in turn reduces the sensitivity of NSCLC cells with wild-type EGFR (EGFR(WT)) to EGFR TKI by repressing expression of liver kinase B1 (LKB1), a master kinase of the AMPK subfamily, via CpG island methylation. In addition, LKB1 expression is correlated positively with sensitivity to TKI in patients with NSCLC. Moreover, combined treatment of EGFR TKI with AMPK activators synergistically increases EGFR TKI sensitivity. Collectively, the current study suggests that LKB1 may serve as a marker to predict EGFR TKI sensitivity in smokers with NSCLC carrying EGFR(WT) and that the combination of EGFR TKI and AMPK activator may be a potentially effective therapeutic strategy against NSCLC with EGFR(WT).

Automated summary

Smokers with non-small cell lung cancer have lower sensitivity to EGFR tyrosine kinase inhibitors, as exposure to cigarette smoke extract enhances glycolysis and weakens the inhibition of mTOR by AMPK, thus reducing the sensitivity of NSCLC cells to EGFR TKI by repressing LKB1 expression. Additionally, LKB1 expression is positively correlated with TKI sensitivity in NSCLC patients, and combined treatment with EGFR TKI and AMPK activators increases TKI sensitivity synergistically.