Targeting ADRB2 enhances sensitivity of non-small cell lung cancer to VEGFR2 tyrosine kinase inhibitors

Abstract

Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) tyrosine kinase inhibitors (TKIs) have achieved remarkable clinical progress in the treatment of non-small-cell lung cancer; however, resistance has limited their therapeutic efficacy. Therefore, understanding the mechanisms of VEGF-TKI and ICI resistance will help to develop effective treatment strategies for patients with advanced NSCLC. Our results suggested that treatment with VEGFR2-TKIs upregulated ADRB2 expression in NSCLC cells. Propranolol, a common ADRB2 antagonist, significantly enhanced the therapeutic effect of VEGFR2-TKIs by inhibiting the ADRB2 signaling pathway in NSCLC cells in vitro and in vivo. Mechanically, the treatment-induced ADRB2 upregulation and the enhancement of ADRB2/VEGFR2 interaction caused resistance to VEGFR2-TKIs in NSCLC. And the inhibition of the ADRB2/CREB/PSAT1 signaling pathway sensitized cells to VEGFR2-TKIs. We demonstrated that ADRB2 signaling is crucial in mediating resistance to VEGFR2-TKIs and provided a novel promising combinatory approach to enhance the antitumor effect of VEGFR2-TKIs in NSCLC combining with propranolol.

Targeting the β2‐adrenergic receptor increases chemosensitivity in multiple myeloma by induction of apoptosis and modulating cancer cell metabolism

“…Our data clearly demonstrated that either selective or non-selective targeting of the β 2 AR subtype is important to exert antitumor effects in multiple myeloma. We observed a heterogeneous βAR expression and response to β-blocker therapy in the tested multiple myeloma patients' samples, which could potentially be attributed to differences in disease stage, tumor progression, and therapy, as already reported for other cancer types [30,31].…”

Comprehensive analysis of a novel signature incorporating lipid metabolism and immune-related genes for assessing prognosis and immune landscape in lung adenocarcinoma

“…The ADRB2 gene encodes the beta2-adrenergic receptor ( β 2-AR), which plays a crucial role in facilitating bronchodilation ( 47 ). Studies have shown that targeting ADRB2 could enhance the sensitivity of lung cancer cells to VEGFR2-TKIs ( 48 ), but the protective mechanism of ADRB2 on LUAD has not been mentioned in the literature. The binding of leucine-rich repeat-containing G-protein-coupled receptor 4 ( LGR4 ) to its receptor R-spondin was reported to promote the proliferation and metastasis of cancer cells.…”

Single B Cell Gene Co-Expression Networks Implicated in Prognosis, Proliferation, and Therapeutic Responses in Non-Small Cell Lung Cancer Bulk Tumors

“…HRH1 protein expression was associated with sensitivity to pemetrexed (Table 2). HRH1 was reported as an apatinib (VEGFR2 inhibitor) upregulated gene and was also associated with neuroactive ligand in NSCLC cells [94]. HRH1 had different prognostic implications in various cancer types [95].…”