针对化学耐药的三阴性乳腺癌中的化和化
Reid T Powell1, Amanda L Rinkenbaugh2, Lei Guo1
1Center for Translational Cancer Research, Institute of Bioscience and Technology Texas A&M Health Science Center, Houston, TX, USA.
NPJ breast cancer
|May 27, 2024
概括
准蛋白质稳态通路,特别是缩,显示出治疗耐化学反应的三阴性乳腺癌 (TNBC) 的前景. 作为NAE抑制剂的pevonedistat在临床前模型中显示出有效性,为TNBC患者提供了新的治疗途径.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 三阴性乳腺癌 (TNBC) 占美国乳腺癌病例的15-20%.
- 新辅助化疗 (NACT) 是早期TNBC的标准,但高达70%的患者在治疗后表现出残留疾病.
- 在NACT后的残留疾病与TNBC早期复发的高风险有关.
研究的目的:
- 为了确定耐化学性TNBC的可针对性漏洞.
- 调查针对TNBC中蛋白质稳态通路的有效性.
- 评估pevonedistat,一个NAE抑制剂,作为TNBC的潜在治疗剂.
主要方法:
- 从NACT前后的TNBC瘤中生成纵向患者衍生异种移植 (PDX) 模型.
- 转录组分析和PDX模型的药物反应概况.
- 在TNBC模型中pevonedistat疗效的体外和体内验证.
主要成果:
- 转录组分析显示,在NACT后的TNBC模型中,异常蛋白质平衡途径的丰富.
- 后NACT模型显示对蛋白酶体,热冲击蛋白和缩途径抑制剂的敏感性增加.
- 在多个TNBC PDX模型中,Pevonedistat在体内表现出单剂疗效.
- 药物转录组分析将尼迪斯塔特活性与翻译后修饰 (PTM) 途径相关联,特别是基和基.
- 较高的NEDD8和SUMO1水平与有利的佩文尼迪斯塔特反应相关.
结论:
- 针对异常的蛋白质稳态通路,包括缩,为抗化学性TNBC提供了可行的策略.
- 佩沃尼迪斯塔特作为TNBC的单一药物显示了治疗潜力.
- 化调节的途径是克服TNBC化学抵抗的关键指标和潜在目标.
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