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

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance is a significant clinical challenge in non-small cell lung cancer (NSCLC).
• T790M-independent resistance mechanisms require identification for improved therapeutic strategies.

Purpose of the Study:

• To elucidate a novel mechanism of EGFR TKI resistance mediated by stress hormones.
• To investigate the role of beta-2 adrenergic receptors (β2-ARs) and interleukin-6 (IL-6) in EGFR TKI resistance.
• To evaluate the therapeutic potential of β-blockers and IL-6 inhibition in overcoming resistance.

Main Methods:

• Investigated the signaling pathway involving stress hormones, β2-ARs, mutant EGFR, liver kinase B1 (LKB1), and IL-6 in NSCLC cells.
• Assessed the impact of stress and β2-AR activation on tumor growth and EGFR TKI response in preclinical models.
• Correlated IL-6 levels and β-blocker use with clinical outcomes in EGFR TKI-treated NSCLC patients.

Main Results:

• Stress hormone-induced β2-AR activation cooperates with mutant EGFR, inactivating LKB1 and upregulating IL-6.
• Activation of this pathway promotes tumor growth and confers resistance to EGFR TKIs.
• Treatment with β-blockers or IL-6 inhibition abrogates stress-induced resistance.
• Elevated IL-6 levels correlate with poorer outcomes in EGFR TKI-treated NSCLC patients.
• β-blocker use is associated with reduced IL-6 and improved efficacy of EGFR TKIs.

Conclusions:

• Chronic stress hormones promote EGFR TKI resistance through a β2-AR/LKB1/CREB/IL-6 signaling axis.
• Targeting β2-ARs with β-blockers represents a promising strategy to overcome EGFR TKI resistance in NSCLC.
• Combination therapy with β-blockers and EGFR TKIs warrants further clinical investigation.