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 beta2-adrenergic receptors (β2-AR) on NSCLC cells, which cooperatively signal with mutant EGFR, resulting in the inactivation of the tumor suppressor, liver kinase B1 (LKB1), and subsequently induce IL-6 expression. We show that stress and β2-AR activation promote tumor growth and EGFR inhibitor resistance, which can be abrogated with beta blockers or IL-6 inhibition. IL-6 was associated with worse outcome in EGFR TKI-treated NSCLC patients, and beta 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/IL-6-dependent mechanism and suggest that combinations of beta blockers with EGFR TKIs merit further investigation as a strategy to abrogate resistance.

Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer

“…8a). In addition, EGFR-mutant NSCLC cell lines HCC4006 and HCC827, having undergone EMT owing to erlotinib resistance (ER) 35 , were also resistant to poziotinib (average IC 50 value of seven ER cell lines = 8.6 μM; Supplementary Fig. 8b).…”

“…All cell lines were free of mycoplasma. Two erlotinib-resistant cell lines were generated as previously described 35 ; briefly, we cultured HCC827 and HCC4006 (both with mutated EGFR ) cells with increasing concentrations of erlotinib until resistant variants emerged.…”

Comprehensive analysis of microRNA‐messenger RNA regulatory network in gemcitabine‐resistant bladder cancer cells

“…25,26 In current study, a total of 536 upregulated and 513 downregulated were screened and mainly enriched in 34 BP terms and 3 KEGG pathways. 31 The upregulation of TNF (degree = 20) was reported to involve in chemoresistance in breast cancer cells to doxorubicin. In addition, a miRNA-DEGs regulatory network, consisting of 18 miRNAs and potential 185 targeted DEGs, was constructed based on predictive analysis of current DEGs and reported miRNA-related GEM resistance.…”

Repurposing established cyclic adenosine monophosphate reducing agents for the prevention and therapy of epidermal growth factor receptor inhibitor resistance in non-small cell lung cancer

“…The investigators additionally found a positive association of high IL-6 levels with the development of EGFR inhibitor resistance in NSCLC patients and improved responsiveness to EGFR kinase inhibitor therapy in NSCLC patients with incidental β-blocker therapy (19). These findings are of immediate high clinical relevance as they suggest the off-label use of not only general β-blockers as concluded by the authors (19) but also other cAMPinhibiting agents ( Table 1) as promising adjunct therapy in NSCLC patients for the prevention and treatment of EGFR inhibitor resistance.…”

“…A recent publication in Sci Transl Med (19) has reported a novel regulatory function of β-ARs in EGFR mutant NSCLC cell lines exposed to epinephrine and in mouse xenografts under psychological stress conditions: the β 2 -AR-mediated, cAMP-dependent promotion of EGFR inhibitor resistance via inactivation of tumor suppressing liver kinase B1 (LKB1), an effect caused by the β 2 -ARstimulated release of interleukin-6 (IL-6) and abrogated by the general β-blocker propranolol or IL-6 antibodies. The investigators additionally found a positive association of high IL-6 levels with the development of EGFR inhibitor resistance in NSCLC patients and improved responsiveness to EGFR kinase inhibitor therapy in NSCLC patients with incidental β-blocker therapy (19).…”