三阴性乳腺癌（TNBC）是目前唯一缺乏有效靶向治疗的亚型。紫杉醇是 TNBC 的主要化疗药物。然而，在 TNBC 患者的治疗过程中经常会出现紫杉醇耐药，这对 TNBC 患者的高死亡率和不良预后有重要影响。最近的临床前研究表明，γ-分泌酶抑制剂抑制Notch通路可以减缓TNBC的进展。我们对乳腺癌患者和TNBC/Taxol细胞体外生物信息分析的研究表明，Notch通路的激活与TNBC中Taxol耐药性之间存在高度相关性。 γ-分泌酶活性的增加（通过催化核心 PSEN-1 的过度表达）显着降低了 TNBC 细胞对紫杉醇的敏感性，并增强了体外恶性肿瘤和体内肿瘤生长的生物学特性。从机制上讲，γ分泌酶活性增加导致NICD在细胞核内积累，促进NICD与PXR相互作用激活PXR，从而触发PXR下游相关耐药基因的转录。此外，我们表明，用 γ-分泌酶抑制剂（Nirogacestat 和 DAPT）对 γ-分泌酶进行药理学抑制可以逆转体内和体外紫杉醇耐药性。我们的研究结果首次证明γ-分泌酶/NCD-PXR/Notch通路的激活是导致TNBC紫杉醇耐药的重要机制之一，对该通路的阻断可能代表着克服TNBC紫杉醇耐药的新治疗策略。 TNBC.版权所有 © 2024。由 Elsevier Inc. 出版。

Triple-negative breast cancer (TNBC) is currently the only subtype lacking efficient targeted therapies. Taxol is the primary chemotherapeutic agent for TNBC. However, Taxol resistance often develops in the treatment of TNBC patients, which importantly contributes to high mortality and poor prognosis in TNBC patients. Recent preclinical studies have shown that the inhibition of Notch pathway by γ-secretase inhibitors can slow down the progression of TNBC. Our studies in bioinformatic analysis of breast cancer patients and TNBC/Taxol cells in vitro showed that there was high correlation between the activation of Notch pathway and Taxol resistance in TNBC. Increased γ-secretase activity (by the overexpression of catalytic core PSEN-1) significantly reduced Taxol sensitivity of TNBC cells, and enhanced biological characteristics of malignancy in vitro, and tumour growth in vivo. Mechanistically, increased γ-secretase activity led to the accumulation of NICD in the nucleus, promoting the interaction between NICD and PXR to activate PXR, which triggered the transcription of PXR downstream associated drug resistance genes. Furthermore, we showed that pharmacological inhibition of γ-secretase with γ-secretase inhibitors (Nirogacestat and DAPT) can reverse Taxol resistance in vivo and in vitro. Our results for the first time demonstrate that the activation of γ -secretase/NCD-PXR/Notch pathway is one of important mechanisms to cause Taxol resistance in TNBC, and the blockades of this pathway may represent a new therapeutic strategy for overcoming Taxol resistance in TNBC.Copyright © 2024. Published by Elsevier Inc.