在ER+乳腺癌中的内分泌持续性伴随着氧化酸化中的代谢脆弱性
bioRxiv : the preprint server for biology
|October 10, 2024
概括
雌激素受体阳性乳腺癌细胞在内分泌治疗中幸存下来,依赖于线粒体. 针对这种线粒体依赖性提供了一个新的策略来预防癌症复发.
科学领域:
- 在瘤学瘤学.
- 癌症新陈代谢 癌症新陈代谢
- 乳腺癌研究研究 乳腺癌研究
背景情况:
- 雌激素受体阳性 (ER+) 乳腺癌可能会复发,尽管内分泌治疗由于癌细胞持久.
- 这些内分泌耐受性持久细胞具有形成瘤的潜力,导致疾病复发.
研究的目的:
- 为了确定内分泌耐受性持久性ER+乳腺癌细胞的脆弱性.
- 探索针对持续性细胞生存机制的治疗策略.
主要方法:
- 使用CRISPR-Cas9全基因组淘汰查,以确定持续的细胞生存机制.
- 定量蛋白质基因分析和代谢追踪以分析持久性细胞代谢.
- 来自第二阶段临床试验 (NCT04568616) 的瘤样本分析,评估新辅助内分泌疗法.
- 使用异种移植的体内研究来评估线粒体复合物I抑制与内分泌治疗相结合的疗效.
主要成果:
- 持久性ER+乳腺癌细胞表现出代谢重编程,依靠线粒体呼吸来产生ATP,这是由于减少了糖分解的原因.
- 在新辅助莱特治疗后,在残留的瘤细胞中观察到线粒体含量增加.
- 药理上抑制线粒体复合体I抑制了持续性细胞瘤形成潜力.
- 组合抑制线粒体复合物I和富尔韦斯特兰特协同诱导患者衍生异体移植的回归.
结论:
- 线粒体代谢是内分泌耐受性持久ER+乳腺癌细胞的关键漏洞.
- 准线粒体呼吸是预防ER+乳腺癌复发的有希望的治疗途径.
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