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Sci Transl Med. 2017 Nov 8;9(415). pii: eaao4307. doi: 10.1126/scitranslmed.aao4307.

Stress hormones promote EGFR inhibitor resistance in NSCLC: Implications for combinations with β-blockers.

Author information

1
Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
2
Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
3
Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
4
Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
5
AstraZeneca, Melbourn, SG8 6EE, UK.
6
Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
7
Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
8
Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.
9
Graduate Institute of Oncology, National Taiwan University and National Taiwan University Hospital, Taipei City 100, Taiwan.
10
Solid Tumor Oncology and Investigational Therapeutics, Levine Cancer Institute Carolinas HealthCare System, Charlotte, NC 28204, USA.
11
Section of Medical Oncology, Yale Cancer Center and Smilow Cancer Hospital, Yale, New Haven, CT 06510, USA.
12
Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
13
Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. jheymach@mdanderson.org.

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 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 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 β-blockers with EGFR TKIs merit further investigation as a strategy to abrogate resistance.

PMID:
29118262
PMCID:
PMC5870120
DOI:
10.1126/scitranslmed.aao4307
[Indexed for MEDLINE]
Free PMC Article

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