By attenuating treatment resistance, beta (β)-blockers may improve clinical outcomes among patients with non–small cell lung cancer (NSCLC) receiving an EGFR inhibitor, according to a hypothesis-generating study published in Science Translational Medicine.1

Though second- and third-generation EGFR inhibitors have efficacy against resistant disease caused by the T790M mutation, about 50% of patients have disease resistant because of another mechanism. This study evaluated stress hormones as a potential mechanism driving T790M-independent EGFR inhibitor resistance using in vitro techniques and assessed clinical outcomes using data from 3 clinical trials.

Preclinical Findings

“We knew from our previous studies that stress hormones cause dramatic increases in IL [interleukin]-6 in ovarian cancer cells. That led us to ask the question whether stress hormones could also increase IL-6 expression in NSCLC cells and in turn promote resistance to EGFR-targeted therapies,” Monique B. Nilsson, PhD, of the University of Texas MD Anderson Cancer Center in Houston, and lead author of the study, told Cancer Therapy Advisor.

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The study demonstrated that EGFR tyrosine kinase inhibitor (TKI)–resistant NSCLC cell lines had significantly greater mRNA expression of IL-6 compared with nonresistant parental cells (P = .0005).

The stress hormones norepinephrine and epinephrine, as well as β-adrenergic agonists, induced IL-6 mRNA expression in the resistant NSCLC cell lines, but not in normal human bronchial epithelial cells. β-adrenergic antagonists, however, prevented norepinephrine from inducing IL-6 expression. 

In a xenograft mouse model, in which the EGFR TKI–resistant NSCLC cells were injected into mice, stress resulted in significantly higher IL-6 levels (P = .002) and over 2-fold greater tumor volumes (P ≤ .04) compared with mice who were not stressed. Xenograft mice treated with a β-adrenergic agonist also demonstrated greater levels of IL-6 mRNA.

Treatment of the xenograft mice with erlotinib resulted in tumor regression, but mice treated with erlotinib plus the β-adrenergic agonist became treatment resistant. The addition of a β-blocker or the anti-IL-6 antibody siltuximab to erlotinib and the β-adrenergic agonist, however, prevented the development of treatment resistance.

These data suggest that blocking the β-adrenergic receptor or IL-6 may prevent erlotinib resistance, even in the presence of a β-adrenergic agonist.