Nilsson M.BSun HDiao LTong PLiu DLi LFan YPoteete ALim S.-OHowells KHaddad VGomez DTran HPena G.ASequist L.VCHIH-HSIN YANGWang JKim E.SHerbst RLee J.JHong W.KWistuba IHung M.-CSood A.KHeymach J.V.2020-05-262020-05-2620171946-6234https://www.scopus.com/inward/record.uri?eid=2-s2.0-85033670124&doi=10.1126%2fscitranslmed.aao4307&partnerID=40&md5=0769358a339f9fc2f113b6d845055713https://scholars.lib.ntu.edu.tw/handle/123456789/494936Epidermal 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 b-blockers or IL-6 inhibition. IL-6 was associated with a worse outcome in EGFR TKI-treated NSCLC patients, and b-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 b-blockers with EGFR TKIs merit further investigation as a strategy to abrogate resistance. ? 2017 The Authors.[SDGs]SDG3afatinib; beta 2 adrenergic receptor; beta adrenergic receptor blocking agent; cisplatin; cyclic AMP responsive element binding protein; epidermal growth factor receptor kinase inhibitor; erlotinib; interleukin 6; interleukin 6 antibody; isoprenaline; liver kinase B1; pemetrexed; propranolol; siltuximab; stress hormone; tumor suppressor protein; unclassified drug; afatinib; beta adrenergic receptor; beta adrenergic receptor blocking agent; cyclic AMP responsive element binding protein; epidermal growth factor receptor; epinephrine; interleukin 6; noradrenalin; protein kinase C; protein kinase inhibitor; protein serine threonine kinase; quinazoline derivative; STK11 protein, human; animal experiment; animal model; Article; cancer combination chemotherapy; cancer resistance; controlled study; disease association; disease course; drug targeting; enzyme inhibition; female; hormonal regulation; human; human cell; lung non-small cell carcinoma cell line; metastasis; mouse; mutant; non small cell lung cancer; nonhuman; overall survival; phase 3 clinical trial (topic); priority journal; progression free survival; protein expression; protein microarray; randomized controlled trial (topic); signal transduction; stress; treatment outcome; tumor growth; antagonists and inhibitors; drug effect; drug resistance; drug screening; genetics; lung tumor; metabolism; mutation; non small cell lung cancer; pathology; tumor cell line; Adrenergic beta-Antagonists; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cyclic AMP Response Element-Binding Protein; Drug Resistance, Neoplasm; Epinephrine; Humans; Interleukin-6; Lung Neoplasms; Mutation; Norepinephrine; Protein Kinase C; Protein Kinase Inhibitors; Protein-Serine-Threonine Kinases; Quinazolines; Receptor, Epidermal Growth Factor; Receptors, Adrenergic, beta; Signal Transduction; Xenograft Model Antitumor Assaysjournal article10.1126/scitranslmed.aao4307291182622-s2.0-85033670124