代谢再连接促进乳腺癌内分泌疗法抵抗力
Songyeon Ahn1, Jun Hyoung Park1, Sandra L Grimm2
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
Cancer research
|October 31, 2023
概括
增加脂肪酸氧化 (FAO) 的代谢重编程通过激活Src信号来驱动雌激素受体阳性乳腺癌的内分泌治疗抵抗. 针对FAO和SRC可以克服这种阻力.
科学领域:
- 在瘤学瘤学.
- 代谢研究研究 代谢研究
- 分子生物学分子生物学
背景情况:
- 内分泌治疗耐药性是雌激素受体阳性 (ER +) 乳腺癌的一个主要挑战,影响约三分之一的患者.
- 了解耐药机制对于改善治疗结果至关重要.
- 线粒体脂肪酸β-氧化 (FAO) 与三阴性乳腺癌 (TNBC) 和Src信号激活有关.
研究的目的:
- 调查新陈代谢重编程,特别是增加粮农组织,作为ER+乳腺癌内分泌治疗耐药性的机制.
- 通过准代谢途径和信号级联,确定克服内分泌抵抗的治疗策略.
主要方法:
- 来自TNBC细胞的转录组,代谢组和脂质组数据的综合分析,以获得基因签名.
- 在ER+乳腺癌模型中进行分子,遗传和代谢学实验 (体外和体内).
- 对卡尼丁棕基转移酶1 (CPT1) 抑制,FAO 抑制剂和Src 抑制剂的评估.
主要成果:
- 与粮农组织和CPT1抑制相关的TNBC衍生的基因特征与ER+乳腺癌患者的内分泌抵抗相关.
- 内分泌疗法诱导了代谢重编程,增加了FAO和激活AMPK-FAO-氧化酸化 (OXPHOS) 信号在耐药ER+乳腺癌中.
- 抑制CPT1或FAO抑制剂增强了内分泌治疗反应;Src抑制剂抑制了抗性瘤生长,与CPT1抑制结合时具有协同效应.
结论:
- 代谢重编程以增加FAO是驱动ER+乳腺癌内分泌治疗耐药性的关键机制.
- 这种FAO激活通过调节Src信号通路来促进抵抗.
- 针对FAO (例如,CPT1抑制) 和Src信号提供了一个有希望的治疗策略,以克服ER+乳腺癌中的内分泌抵抗.
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