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

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.

• Authors: Monique B Nilsson, Huiying Sun, Lixia Diao, Pan Tong, Diane Liu, Lerong Li, Youhong Fan, Alissa Poteete, Seung-Oe Lim, Kathryn Howells, Vincent Haddad, Daniel Gomez, Hai Tran, Guillermo Armaiz Pena, Lecia V Sequist, James C Yang, Jing Wang, Edward S Kim, Roy Herbst, J Jack Lee, Waun Ki Hong, Ignacio Wistuba, Mien-Chie Hung, Anil K Sood, John V Heymach
• Journal: Science translational medicine (Sci Transl Med) Vol. 9 Issue 415 (Nov 08 2017) ISSN: 1946-6242 [Electronic] United States
• PMID: 29118262 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Adrenergic beta-Antagonists
• Cyclic AMP Response Element-Binding Protein
• Interleukin-6
• Protein Kinase Inhibitors
• Quinazolines
• Receptors, Adrenergic, beta
• Afatinib
• ErbB Receptors
• Protein Serine-Threonine Kinases
• STK11 protein, human
• Protein Kinase C
• AMP-Activated Protein Kinase Kinases
• Norepinephrine
• Epinephrine

Topics

• AMP-Activated Protein Kinase Kinases
• Adrenergic beta-Antagonists (pharmacology, therapeutic use)
• Afatinib
• Carcinoma, Non-Small-Cell Lung (drug therapy, pathology)
• Cell Line, Tumor
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Drug Resistance, Neoplasm (drug effects)
• Epinephrine (pharmacology)
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Humans
• Interleukin-6 (metabolism)
• Lung Neoplasms (drug therapy, pathology)
• Mutation (genetics)
• Norepinephrine (pharmacology)
• Protein Kinase C (metabolism)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Protein Serine-Threonine Kinases (metabolism)
• Quinazolines (pharmacology, therapeutic use)
• Receptors, Adrenergic, beta (metabolism)
• Signal Transduction
• Xenograft Model Antitumor Assays