In:
Science Translational Medicine, American Association for the Advancement of Science (AAAS), Vol. 9, No. 415 ( 2017-11-08)
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 β 2 -adrenergic receptors (β 2 -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 2 -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 2 -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.
Type of Medium:
Online Resource
ISSN:
1946-6234
,
1946-6242
DOI:
10.1126/scitranslmed.aao4307
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2017