PDF(Pubmed)
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.
摘要：
对表皮生长因子酪氨酸激酶抑制剂（EGFR-TKI）的耐药性仍然是肺腺癌（LUAD）治疗的主要挑战之一。这里,我们发现EGFR-TKI敏感患者NOTCH4信号肽区(NOTCH4ΔL12_16)L12_16氨基酸缺失突变频率增加。功能上,在EGFR-TKI耐药的LUAD细胞中外源性诱导NOTCH4ΔL12_16使其对EGFR-TKIs敏感。此过程主要由NOTCH4ΔL12_16突变引起的NOTCH4（NICD4）胞内结构域的减少介导，这导致NOTCH4在质膜中的较低定位。机械上,相对于p-STAT3，NICD4通过竞争性结合基因启动子在转录上上调HES1的表达。因为p-STAT3可以下调HES1在EGFR-TKI耐药LUAD细胞中的表达，NOTCH4ΔL12_16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途径可以消除EGFR-TKI的耐药性。总的来说,我们报告说，NOTCH4ΔL12_16突变通过HES1的转录下调使LUAD患者对EGFR-TKIs敏感，并且该信号队列的靶向阻断可以逆转LUAD中的EGFR-TKI耐药，提供了一种克服EGFR-TKI治疗耐药性的潜在方法。
