南方科技大学知识苑(SUSTech KC): NOTCH4ΔL12_16 sensitizes lung adenocarcinomas to EGFR-TKIs through transcriptional down-regulation of HES1

题名	NOTCH4ΔL12_16 sensitizes lung adenocarcinomas to EGFR-TKIs through transcriptional down-regulation of HES1
作者	Zhang，Bin 1 ; Dong，Shaowei 2; Wang，Jian 1 ; Huang，Tuxiong 3; Zhao，Pan1 ; Xu，Jing 1 ; Liu，Dongcheng 1; Fu，Li 3; Wang，Lingwei 1; Wang，Guangsuo 1; Zou，Chang 1,4
通讯作者	Zou，Chang
发表日期	2023-12-01
DOI	10.1038/s41467-023-38833-7
发表期刊	Nature Communications 影响因子和分区
EISSN	2041-1723
卷号	14 期号:1
摘要	Resistance to epidermal growth factor tyrosine kinase inhibitors (EGFR-TKI) remains one of the major challenges in lung adenocarcinoma (LUAD) therapy. Here, we find an increased frequency of the L12_16 amino acid deletion mutation in the signal peptide region of NOTCH4 (NOTCH4) in EGFR-TKI-sensitive patients. Functionally, exogenous induction of NOTCH4 in EGFR-TKI -resistant LUAD cells sensitizes them to EGFR-TKIs. This process is mainly mediated by the reduction of the intracellular domain of NOTCH4 (NICD4) caused by the NOTCH4 mutation, which results in a lower localization of NOTCH4 in the plasma membrane. Mechanistically, NICD4 transcriptionally upregulates the expression of HES1 by competitively binding to the gene promoter relative to p-STAT3. Because p-STAT3 can downregulate the expression of HES1 in EGFR-TKI-resistant LUAD cells, the reduction of NICD4 induced by NOTCH4 mutation leads to a decrease in HES1. Moreover, inhibition of the NOTCH4-HES1 pathway using inhibitors and siRNAs abolishes the resistance of EGFR-TKI. Overall, we report that the NOTCH4 mutation sensitizes LUAD patients to EGFR-TKIs through transcriptional down-regulation of HES1 and that targeted blockade of this signaling cohort could reverse EGFR-TKI -resistance in LUAD, providing a potential approach to overcome resistance to EGFR-TKI -therapy.
相关链接	[Scopus记录]
收录类别	SCI
语种	英语
重要成果	NI论文
学校署名	第一 ; 通讯
资助项目	Guangdong Basic and Applied Basic Research Foundation[2020B1515120032] ; Shenzhen Key Medical Discipline Construction Fund[SZXK018] ; Guangdong Provincial Natural Science Foundation[2021A1515010919] ; Guangdong Province Medical Research Fund Project[A2020508] ; Shenzhen Science and Technology Program[JCYJ20210324113008020] ; National Natural Science Foundation of China[32100609]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:001003996200023
出版者	NATURE PORTFOLIO
Scopus记录号	2-s2.0-85160893100
来源库	Scopus
引用统计	被引频次[WOS]：2
成果类型	期刊论文
条目标识符	http://sustech.caswiz.com/handle/2SGJ60CL/559468
专题	南方科技大学第一附属医院
作者单位	1.Department of Respiratory and Critical Care Medicine,The First Affiliated Hospital,Southern University of Science and Technology,Shenzhen,Guangdong,China 2.Department of Hematology and Oncology,Shenzhen Children’s Hospital,Shenzhen,Guangdong,China 3.Department of Pharmacology and International Cancer Center,Shenzhen University Medical School,Shenzhen,Guangdong,China 4.School of Medicine,Life and Health Sciences,The Chinese University of Hong Kong (Shenzhen),Shenzhen,Guangdong,China
第一作者单位	南方科技大学第一附属医院
通讯作者单位	南方科技大学第一附属医院
第一作者的第一单位	南方科技大学第一附属医院
推荐引用方式 GB/T 7714	Zhang，Bin,Dong，Shaowei,Wang，Jian,et al. NOTCH4ΔL12_16 sensitizes lung adenocarcinomas to EGFR-TKIs through transcriptional down-regulation of HES1[J]. Nature Communications,2023,14(1).
APA	Zhang，Bin.,Dong，Shaowei.,Wang，Jian.,Huang，Tuxiong.,Zhao，Pan.,...&Zou，Chang.(2023).NOTCH4ΔL12_16 sensitizes lung adenocarcinomas to EGFR-TKIs through transcriptional down-regulation of HES1.Nature Communications,14(1).
MLA	Zhang，Bin,et al."NOTCH4ΔL12_16 sensitizes lung adenocarcinomas to EGFR-TKIs through transcriptional down-regulation of HES1".Nature Communications 14.1(2023).