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

Bin Zhang, Shaowei Dong, Jian Wang, Tuxiong Huang, Pan Zhao, Jing Xu, Dongcheng Liu, Li Fu, Lingwei Wang, Guangsuo Wang and Chang Zou ()
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Bin Zhang: Southern University of Science and Technology
Shaowei Dong: Shenzhen Children’s Hospital
Jian Wang: Southern University of Science and Technology
Tuxiong Huang: Shenzhen University Medical School
Pan Zhao: Southern University of Science and Technology
Jing Xu: Southern University of Science and Technology
Dongcheng Liu: Southern University of Science and Technology
Li Fu: Shenzhen University Medical School
Lingwei Wang: Southern University of Science and Technology
Guangsuo Wang: Southern University of Science and Technology
Chang Zou: Southern University of Science and Technology

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract 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 (NOTCH4ΔL12_16) in EGFR-TKI-sensitive patients. Functionally, exogenous induction of NOTCH4ΔL12_16 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 NOTCH4ΔL12_16 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 NOTCH4ΔL12_16 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 NOTCH4ΔL12_16 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.

Date: 2023
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DOI: 10.1038/s41467-023-38833-7

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