Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Sci Transl Med. 2017 Nov 8;9(415). doi: 10.1126/scitranslmed.aao4307.
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 β-adrenergic receptors (β-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 β-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 β-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.
表皮生长因子受体 (EGFR) 酪氨酸激酶抑制剂 (TKI) 耐药性由 T790M 独立机制介导，仍然是治疗非小细胞肺癌 (NSCLC) 的主要挑战。我们确定了一种可靶向的 EGFR 抑制剂耐药机制，即应激激素激活 NSCLC 细胞上的β-肾上腺素能受体 (β-AR)，与突变型 EGFR 协同信号传导，导致肿瘤抑制因子肝激酶 B1 (LKB1) 失活，随后诱导白细胞介素 6 (IL-6) 的表达。我们表明，应激和β-AR 激活促进肿瘤生长和 EGFR 抑制剂耐药性，可通过β受体阻滞剂或 IL-6 抑制来阻断。IL-6 与接受 EGFR TKI 治疗的 NSCLC 患者的不良预后相关，β受体阻滞剂的使用与较低的 IL-6 浓度和提高 EGFR 抑制剂的获益相关。这些发现提供了证据表明，慢性应激激素通过 LKB1/CREB（环磷酸腺苷 3'，5'-单磷酸反应元件结合蛋白）/IL-6 依赖性机制通过β-AR 信号传导促进 EGFR TKI 耐药性，并表明β受体阻滞剂与 EGFR TKI 的联合使用值得进一步研究，作为一种克服耐药性的策略。
