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.
Original language | English (US) |
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Article number | 4307 |
Journal | Science translational medicine |
Volume | 9 |
Issue number | 415 |
DOIs | |
State | Published - Nov 8 2017 |
ASJC Scopus subject areas
- General Medicine
MD Anderson CCSG core facilities
- Bioinformatics Shared Resource
- Biostatistics Resource Group