5 years ago

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

John V Heymach, J Jack Lee, Monique B Nilsson, Lecia V Sequist, Daniel Gomez, Youhong Fan, Waun Ki Hong, Hai Tran, Mien-Chie Hung, Edward S Kim, Huiying Sun, Anil K Sood, Alissa Poteete, Roy Herbst, James C Yang, Vincent Haddad, Kathryn Howells, Lerong Li, Guillermo Armaiz Pena, Diane Liu, Ignacio Wistuba, Jing Wang, Lixia Diao, Pan Tong, Seung-Oe Lim
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.

Publisher URL: http://doi.org/10.1126/scitranslmed.aao4307

DOI: 10.1126/scitranslmed.aao4307

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