PO.ET03.02 · 实验与分子治疗
RAC2作为三阴性乳腺癌药物耐药的介导因子
RAC2 as a mediator of drug resistance in triple-negative breast cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
三阴性乳腺癌（TNBC）是一种高度侵袭性和异质性的乳腺癌亚型，其定义为缺乏雌激素受体（ER）、孕激素受体（PR）以及人表皮生长因子受体2（HER2）表达低或缺失。这些治疗靶点的缺乏限制了治疗选择，并导致不良的临床结局。酪氨酸激酶抑制剂（TKIs）通过破坏驱动肿瘤生长和存活的受体酪氨酸激酶（RTK）信号通路，提供了一种靶向方法。然而，由代偿性信号、遗传改变和上皮-间质转化（EMT）介导的耐药的出现，仍是持续治疗疗效的主要障碍。在本研究中，我们假设长期暴露于TKIs会诱导上皮性TNBC细胞的转录重编程，从而促进药物耐药。利用RNA测序，我们分析了对照组和拉帕替尼耐药的MDA-MB-468细胞（一种EGFR/HER2驱动的TNBC模型）中的差异表达基因（DEGs）。我们鉴定出129个DEGs，并通过qPCR和Western blotting验证了其中调控最显著的五个基因。这些基因还与基底样乳腺癌患者的无复发生存相关。值得注意的是，RAC2，一种小型Rho GTP酶，作为一个顶级候选者浮现，在耐药细胞中显示出强劲的上调。与类似的小型GTP酶相比，我们发现这种上调是RAC2特异性的。RAC2表达在TNBC细胞系和患者来源异种移植（PDX）模型中被发现具有异质性，提示存在细胞类型特异性的调控。在MDA-MB-468细胞中异位过表达RAC2，赋予了细胞在拉帕替尼和来那替尼处理后更高的活力，并显著支持了TNBC细胞对来那替尼的耐药。此外，RAC2上调显著增强了迁移和侵袭行为，如Transwell迁移和Matrigel侵袭实验所示。我们的研究结果表明RAC2是TNBC中TKI耐药的一种新型介导因子，并支持其作为恢复耐药TNBC细胞药物敏感性的潜在治疗靶点。
查看英文原文 English abstract
Triple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous subtype of breast cancer, defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and low or absent human epidermal growth factor receptor 2 (HER2) expression. The lack of these therapeutic targets limits treatment options and contributes to poor clinical outcomes. Tyrosine kinase inhibitors (TKIs) offer a targeted approach by disrupting receptor tyrosine kinase (RTK) signaling pathways that drive tumor growth and survival. However, the emergence of resistance, mediated by compensatory signaling, genetic alterations, and epithelial-to-mesenchymal transition (EMT), remains a major barrier to sustained therapeutic efficacy. In this study, we hypothesized that chronic exposure to TKIs induces transcriptional reprogramming in epithelial TNBC cells, promoting drug resistance. Using RNA sequencing, we profiled differentially expressed genes (DEGs) in control and lapatinib-resistant MDA-MB-468 cells, an EGFR/HER2-driven TNBC model. We identified 129 DEGs and validated five of the most significantly modulated genes by qPCR and Western blotting. These genes were also associated with relapse-free survival in basal-like breast cancer patients. Notably, RAC2, a small Rho GTPase, emerged as a top candidate, showing robust upregulation in resistant cells. Compared to similar small GTPases, we found that this upregulation is specific to RAC2. RAC2 expression was found to be heterogeneous across TNBC cell lines and patient-derived xenograft (PDX) models, suggesting cell type-specific regulation. Ectopic overexpression of RAC2 in MDA-MB-468 cells conferred increased viability following treatment with lapatinib and neratinib and supported the resistance of TNBC cells to neratinib significantly. Furthermore, RAC2 upregulation significantly enhanced migratory and invasive behavior, as demonstrated by Transwell migration and Matrigel invasion assays. Our findings implicate RAC2 as a novel mediator of TKI resistance in TNBC and support its potential as a therapeutic target to restore drug sensitivity in resistant TNBC cells.
利益披露 Disclosure
A. R. McIntosh, None..
N. Voung, None..
A. Edwards, None.