Stress hormones promote EGFR inhibitor resistance in NSCLC: Implications for combinations with β-blockers
Journal
Science Translational Medicine
Journal Volume
9
Journal Issue
415
Date Issued
2017
Author(s)
Nilsson M.B
Sun H
Diao L
Tong P
Liu D
Li L
Fan Y
Poteete A
Lim S.-O
Howells K
Haddad V
Gomez D
Tran H
Pena G.A
Sequist L.V
Wang J
Kim E.S
Herbst R
Lee J.J
Hong W.K
Wistuba I
Hung M.-C
Sood A.K
Heymach J.V.
Abstract
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 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
Other Subjects
afatinib; 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 Assays
Publisher
American Association for the Advancement of Science
Type
journal article