Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 9, Issue 415, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aao4307
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Funding
- LUNGevity Foundation
- Lung SPORE [5 P50 CA070907]
- Lung Cancer Moon Shot Program, NIH Cancer Center Support Grant [CA016672]
- Hallman Fund [1R01 CA190628]
- Bruton Endowed Chair in Tumor Biology
- Stading Fund for EGFR inhibitor resistance
- Fox Lung EGFR Inhibitor
- Rexanna Foundation for Fighting Lung Cancer
- American Cancer Society
- [CA109298]
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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 beta(2)-adrenergic receptors (beta(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 beta(2)-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 a 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 beta(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 beta-blockers with EGFR TKIs merit further investigation as a strategy to abrogate resistance.
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