By attenuating treatment resistance, beta 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.
“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.
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.