NOTCH4ΔL12_16 sensitizes lung adenocarcinomas to EGFR-TKIs through transcriptional down-regulation of HES1

Zhang，Bin1; Dong，Shaowei2; Wang，Jian1; Huang，Tuxiong3; Zhao，Pan1; Xu，Jing1; Liu，Dongcheng1; Fu，Li3; Wang，Lingwei1; Wang，Guangsuo1; Zou，Chang1,4

2023-12-01

10.1038/s41467-023-38833-7

Nature Communications   Impact Factor & Quartile

2041-1723

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.

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English

NI Journal Papers ; NI论文

First ; Corresponding

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]

Science & Technology - Other Topics

Multidisciplinary Sciences

WOS:001003996200023

NATURE PORTFOLIO

2-s2.0-85160893100

Scopus

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

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).

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).

Zhang，Bin,et al."NOTCH4ΔL12_16 sensitizes lung adenocarcinomas to EGFR-TKIs through transcriptional down-regulation of HES1".Nature Communications 14.1(2023).