Stress hormones promote EGFR inhibitor resistance in NSCLC: Implications for combinations with β-blockers.
Stress hormones promote EGFR inhibitor resistance in NSCLC: Implications for combinations with β-blockers.
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DOI：
10.1126/scitranslmed.aao4307
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发表时间：
2017-11-08
影响因子：
17.1
通讯作者：
Heymach JV
中科院分区：
文献类型：
--
作者：
Nilsson MB;Sun H;Diao L;Tong P;Liu D;Li L;Fan Y;Poteete A;Lim SO;Howells K;Haddad V;Gomez D;Tran H;Pena GA;Sequist LV;Yang JC;Wang J;Kim ES;Herbst R;Lee JJ;Hong WK;Wistuba I;Hung MC;Sood AK;Heymach JV
由T790 M非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）耐药仍然是非小细胞肺癌（NSCLC）治疗的主要挑战。我们确定了EGFR抑制剂耐药性的一种靶向机制，即应激激素激活NSCLC细胞上的β 2-肾上腺素能受体（β2-AR），后者与突变型EGFR协同发出信号，导致肿瘤抑制因子肝激酶B1（LKB 1）失活，随后诱导IL-6表达。我们发现，应激和β2-AR激活促进肿瘤生长和EGFR抑制剂耐药性，这可以通过β受体阻滞剂或IL-6抑制来消除。IL-6与EGFR TKI治疗的NSCLC患者的结局较差相关，β受体阻滞剂的使用与IL-6浓度降低和EGFR抑制剂获益改善相关。这些结果提供了证据，表明慢性应激激素通过LKB 1/CREB/IL-6依赖性机制通过β2-AR信号传导促进EGFR TKI耐药，并表明β受体阻滞剂与EGFR TKI联合用药作为消除耐药的策略值得进一步研究。
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 beta2-adrenergic receptors (β2-AR) on NSCLC cells, which cooperatively signal with mutant EGFR, resulting in the inactivation of the tumor suppressor, liver kinase B1 (LKB1), and subsequently induce IL-6 expression. We show that stress and β2-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 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 β2-AR signaling by an LKB1/CREB/IL-6-dependent mechanism and suggest that combinations of beta blockers with EGFR TKIs merit further investigation as a strategy to abrogate resistance.
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影响因子：
6.4
作者：
Banerjee J;Papu John AM;Schuller HM
通讯作者：
Schuller HM
DOI：
10.1097/jto.0000000000000173
发表时间：
2014-06
期刊：
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
影响因子：
--
作者：
Kaufman JM;Amann JM;Park K;Arasada RR;Li H;Shyr Y;Carbone DP
通讯作者：
Carbone DP
影响因子：
45.3
作者：
Barron, Thomas I.;Connolly, Roisin M.;Visvanathan, Kala
通讯作者：
Visvanathan, Kala
影响因子：
158.5
作者：
Jaenne, Pasi A.;Yang, James Chih-Hsin;Ranson, Malcolm
通讯作者：
Ranson, Malcolm
DOI：
10.1073/pnas.0911515107
发表时间：
2010-03-23
影响因子：
11.1
作者：
Cole, Steven W.;Arevalo, Jesusa M. G.;Seeman, Teresa E.
通讯作者：
Seeman, Teresa E.