Stress hormones promote EGFR inhibitor resistance in NSCLC: Implications for combinations with β-blockers

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance mediated by T790M-independent mechanisms remains a major challenge in the treatment of non-small cell lung cancer (NSCLC). We identified a targetable mechanism of EGFR inhibitor resistance whereby stress hormones activate beta(2)-adrenergic receptors (beta(2)-ARs) on NSCLC cells, which cooperatively signal with mutant EGFR, resulting in the inactivation of the tumor suppressor, liver kinase B1 (LKB1), and subsequently induce interleukin-6 (IL-6) expression. We show that stress and beta(2)-AR activation promote tumor growth and EGFR inhibitor resistance, which can be abrogated with beta-blockers or IL-6 inhibition. IL-6 was associated with a worse outcome in EGFR TKI-treated NSCLC patients, and beta-blocker use was associated with lower IL-6 concentrations and improved benefit from EGFR inhibitors. These findings provide evidence that chronic stress hormones promote EGFR TKI resistance via beta(2)-AR signaling by an LKB1/CREB (cyclic adenosine 3', 5'-monophosphate response element-binding protein)/IL-6-dependent mechanism and suggest that combinations of beta-blockers with EGFR TKIs merit further investigation as a strategy to abrogate resistance.