文章：

HER2阳性乳腺癌细胞经内源性配体处理后的分子图谱：曲妥珠单抗耐药机制的时间动态解析

Molecular Atlas of HER2+ Breast Cancer Cells Treated with Endogenous Ligands: Temporal Insights into Mechanisms of Trastuzumab Resistance

原文发布日期：27 January 2024

DOI: 10.3390/cancers16030553

类型: Article

开放获取: 是

英文摘要：

Trastuzumab therapy in HER2+ breast cancer patients has mixed success owing to acquired resistance to therapy. A detailed understanding of downstream molecular cascades resulting from trastuzumab resistance is yet to emerge. In this study, we investigate the cellular mechanisms underlying acquired resistance using trastuzumab-sensitive and -resistant cancer cells (BT474 and BT474R) treated with endogenous ligands EGF and HRG across time. We probe early receptor organization through microscopy and signaling events through multiomics measurements and assess the bioenergetic state through mitochondrial measurements. Integrative analyses of our measurements reveal significant alterations in EGF-treated BT474 HER2 membrane dynamics and robust downstream activation of PI3K/AKT/mTORC1 signaling. EGF-treated BT474R shows a sustained interferon-independent activation of the IRF1/STAT1 cascade, potentially contributing to trastuzumab resistance. Both cell lines exhibit temporally divergent metabolic demands and HIF1A-mediated stress responses. BT474R demonstrates inherently increased mitochondrial activity. HRG treatment in BT474R leads to a pronounced reduction in AR expression, affecting downstream lipid metabolism with implications for treatment response. Our results provide novel insights into mechanistic changes underlying ligand treatment in BT474 and BT474R and emphasize the pivotal role of endogenous ligands. These results can serve as a framework for furthering the understanding of trastuzumab resistance, with therapeutic implications for women with acquired resistance.

摘要翻译： 

曲妥珠单抗在治疗HER2阳性乳腺癌患者中疗效不一，主要归因于获得性耐药的出现。目前对于曲妥珠单抗耐药引发的下游分子级联反应机制尚未完全阐明。本研究通过对比曲妥珠单抗敏感型与耐药型癌细胞（BT474与BT474R）在不同时间点经内源性配体EGF和HRG处理后的变化，探究获得性耐药的细胞机制。我们采用显微技术观察早期受体组织变化，通过多组学测量分析信号传导事件，并通过线粒体功能检测评估细胞生物能量状态。整合分析显示：EGF处理的BT474细胞中HER2膜动力学发生显著改变，并强烈激活PI3K/AKT/mTORC1信号通路下游；而EGF处理的BT474R细胞则表现出持续不依赖干扰素的IRF1/STAT1级联激活，这可能是导致曲妥珠单抗耐药的重要因素。两种细胞系均呈现时间差异性的代谢需求及HIF1A介导的应激反应。BT474R细胞表现出固有的线粒体活性增强。HRG处理BT474R细胞导致AR表达显著降低，进而影响下游脂质代谢，这对治疗反应具有潜在影响。本研究揭示了BT474与BT474R细胞在配体处理下发生机制性改变的新见解，并强调了内源性配体的关键作用。这些发现为进一步理解曲妥珠单抗耐药机制提供了理论框架，对获得性耐药乳腺癌患者的治疗具有重要临床意义。

原文链接：

Molecular Atlas of HER2+ Breast Cancer Cells Treated with Endogenous Ligands: Temporal Insights into Mechanisms of Trastuzumab Resistance