Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong, PR China.
Department of Hematology and Oncology, Shenzhen Children's Hospital, Shenzhen, Guangdong, PR China.
Nat Commun. 2023 Jun 2;14(1):3183. doi: 10.1038/s41467-023-38833-7.
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.
表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）耐药仍然是肺腺癌（LUAD）治疗的主要挑战之一。在这里，我们发现在 EGFR-TKI 敏感患者中 NOTCH4（NOTCH4）信号肽区域的 L12_16 氨基酸缺失突变频率增加。功能上，在 EGFR-TKI 耐药的 LUAD 细胞中外源诱导 NOTCH4 使它们对 EGFR-TKIs 敏感。这个过程主要是由 NOTCH4 突变引起的 NOTCH4 细胞内结构域（NICD4）的减少介导的，这导致 NOTCH4 在质膜中的定位降低。从机制上讲，NICD4 通过与基因启动子相对竞争结合来转录上调 HES1 的表达，而不是 p-STAT3。因为 p-STAT3 可以下调 EGFR-TKI 耐药 LUAD 细胞中 HES1 的表达，NOTCH4 突变诱导的 NICD4 减少导致 HES1 减少。此外，使用抑制剂和 siRNA 抑制 NOTCH4-HES1 通路可消除 EGFR-TKI 的耐药性。总的来说，我们报告 NOTCH4 突变通过转录下调 HES1 使 LUAD 患者对 EGFR-TKIs 敏感，靶向阻断这一信号级联可能会逆转 LUAD 中的 EGFR-TKI 耐药性，为克服 EGFR-TKI 治疗耐药性提供了一种潜在方法。
