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氧化酸化是内分泌治疗的代谢脆弱性,也是对palbociclib耐药的转移性乳腺癌的代谢脆弱性

Rania El-Botty¹, Ludivine Morriset¹, Elodie Montaudon¹

¹Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, PSL University, 26 rue d'Ulm, 75005, Paris, France.

Nature communications

|July 14, 2023

概括

一项新的研究显示,一些转移性雌激素受体阳性乳腺癌 (ER+BC) 取决于氧化酸化 (OXPHOS). 一种OXPHOS抑制剂,IACS-010759,有效地减少了耐药模型中的瘤生长,突出了OXPHOS作为潜在的治疗标.

科学领域:

在瘤学瘤学.
代谢途径代谢途径
癌症研究癌症研究

背景情况:

内分泌疗法和CDK4/6抑制剂耐药性在雌激素受体阳性乳腺癌 (ER+BC) 中很常见.
转移ER+BC的一小组表现出对氧化酸化 (OXPHOS) 的强烈依赖,以求生存和繁殖.

研究的目的:

调查OXPHOS在耐治疗ER+BC中的作用.
评估OXPHOS抑制剂IACS-010759在耐药ER+BC的临床前模型中的疗效.

主要方法:

对患者瘤,患者衍生异种移植 (PDX) 和细胞系的基因组和代谢学分析.
在体内对IACS-010759的疗效研究在内分泌和帕尔博西克利布耐药的PDX模型中.
在体外研究评估OXPHOS依赖性和反应性氧物种 (ROS) 水平.

主要成果:

在多重耐药PDX模型中,IACS-010759显著抑制了瘤生长.
PIK3CA/AKT1基因的突变与对IACS-010759.9的反应有关.
在ER+BC患者中,OXPHOS相关基因的高表达预示着预后不佳.

结论:

氧化酸化 (OXPHOS) 是一个关键的弱点,在一个部分的耐治疗ER+BC.
用像IACS-010759这样的抑制剂向OXPHOS显示出克服抵抗的希望.
OXPHOS依赖性和相关的基因表达可能作为治疗反应的预测生物标志物.

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