Targeting ADRB2 Enhances Sensitivity of Non-small Cell Lung Cancer to VEGFR2 Tyrosine Kinase Inhibitors

Overview

Journal Cell Death Discov

Date 2022 Jan 25

PMID 35075132

Authors

Yingzhuo Xu

Jian Wang

Xu Wang

Xiaoshu Zhou

Jing Tang

Xiaohua Jie

Xijie Yang

Xinrui Rao

Yunhong Xu

Biyuan Xing

Zhenyu Li

Gang Wu

Affiliations

Soon will be listed here.

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.

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