Cx32 mediates norepinephrine‐promoted EGFR‐TKI resistance in a gap junction‐independent manner in non‐small‐cell lung cancer

Abstract

The second-generation EGFR-TKI Afatinib is an irreversible ErbB family blocker used to treat patients with non-small-cell lung cancer (NSCLC). Unfortunately, resistance to this drug develops over time, and patients are always under great psychological pressure. A previous study showed that chronic stress hormones participate in EGFR-TKI resistance via β 2 -AR signaling via an IL-6 dependent mechanism. Our study further explores a novel potential underlying mechanism. In the present study, we show that the stress hormone norepinephrine (NE) promotes Afatinib resistance by upregulating Cx32 expression.Furthermore, we, for the first time, find that Cx32 is a target gene for transcription factor CREB and NE enhances Cx32 mRNA expression by activation of CREB. We also demonstrate that Cx32 promotes Afatinib resistance by decreasing the degradation of EGFR-TKI resistance-associated proteins (MET, IGF-1R) and by increasing their transcription levels. Together, these results reveal that the stress hormone NE accelerates Afatinib resistance by increasing the expression of Cx32, which augments MET and IGF-1R levels in cancer cells and provides a promising therapeutic strategy against EGFR-TKI Afatinib resistance in NSCLC. K E Y W O R D SAfatinib, Cx32, drug resistance, norepinephrine, NSCLC

Chronic Stress: Impacts on Tumor Microenvironment and Implications for Anti-Cancer Treatments

“…Chronic stress-induced stress hormone norepinephrine (NE) promotes afatinib resistance by upregulating Cx32 expression which could decrease the degradation of EGFR-TKI resistanceassociated proteins (MET, IGF-1R) and increase their transcription levels (Xie et al, 2019). β2-AR activation on non-small cell lung cancer (NSCLC) cell induces epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance by inactivating liver kinase B1 (LKB1), elevating IL-6 expression, and MAPK pathway in a rodent model (Nilsson et al, 2017).…”

The role of deubiquitinases in cardiac disease

“…Epidermal growth factor receptor (EGFR) is a member of receptor tyrosine kinase whose deficiency could worsen myocardial hypertrophy, cardiac dysfunction and arterial hypotension (Refs 68 , 69 ). A series of classic pro-hypertrophic factors, such as Ang II and norepinephrine, could bind to their cell membrane receptors and activate EGFR (Refs 70 , 71 ). The intracellular tyrosine kinase domain of EGFR actively participates in signal transduction, activating the PI3K/Akt, MAPK and other signalling pathways.…”

Investigating the crosstalk between chronic stress and immune cells: implications for enhanced cancer therapy

“…The research findings indicate that chronic stress impedes the inhibitory effects of EGFR, leading to a decrease in the effectiveness of the treatment. Additionally, the stress hormone NE increases the expression of Cx32 and enhances the transcription levels of proteins associated with resistance to EGFR-TKI, such as MET and IGF-1R ( Xie et al, 2019 ). At the same time, it slows down the degradation rate of these proteins, further worsening the impact on the efficacy of Afatinib.…”