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 β₂-adrenergic receptors (β₂-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 β₂-AR activation promote tumor growth and EGFR inhibitor resistance, which can be abrogated with β-blockers or IL-6 inhibition. IL-6 was associated with a worse outcome in EGFR TKI–treated NSCLC patients, and β-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 β₂-AR signaling by an LKB1/CREB (cyclic adenosine 3′,5′-monophosphate response element–binding protein)/IL-6–dependent mechanism and suggest that combinations of β-blockers with EGFR TKIs merit further investigation as a strategy to abrogate resistance.

由T790M依赖性机制介导的表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）耐药性仍然是治疗非小细胞肺癌（NSCLC）的主要挑战。我们确定EGFR抑制剂抗性的可靶向的机制，由此应激激素激活β ₂ -肾上腺素能受体（β ₂上NSCLC细胞，用突变EGFR其中协同信号-ARs），导致肿瘤抑制，肝激酶B1（LKB1）的失活，并随后诱导白介素6（IL-6）表达。我们发现，压力和β ₂-AR激活可促进肿瘤生长和EGFR抑制剂耐药性，而后者可被β-受体阻滞剂或IL-6抑制所废除。在接受EGFR TKI治疗的NSCLC患者中，IL-6与较差的预后相关，而β受体阻滞剂的使用与较低的IL-6浓度和EGFR抑制剂的获益相​​关。这些结果提供的证据表明慢性应激激素促进经由βEGFR TKI电阻₂ -AR信令由LKB1 / CREB（环腺苷3'，5'-单磷酸反应元件结合蛋白）/ IL-6依赖性机制和建议的组合EGFR TKIs的β受体阻滞剂值得进一步研究，以消除耐药性。