CD36-Mediated Metabolic Rewiring of Breast Cancer Cells Promotes Resistance to HER2-Targeted Therapies
CD36-Mediated Metabolic Rewiring of Breast Cancer Cells Promotes Resistance to HER2-Targeted Therapies
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DOI：
10.1016/j.celrep.2019.11.008
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发表时间：
2019-12-10
期刊：
影响因子：
8.8
通讯作者：
Kurokawa, Manabu
中科院分区：
文献类型：
--
作者：
Feng, William W.;Wilkins, Owen;Kurokawa, Manabu
虽然已经确定脂肪酸（FA）合成支持癌症的合成代谢生长，但外源性FA摄取的作用仍然难以捉摸。在这里，我们表明，在收购耐HER2抑制，乳腺癌细胞的代谢重新布线有利于依赖外源性FA摄取从头FA合成。通过cDNA微阵列分析，我们确定FA转运蛋白CD36作为一个关键基因上调细胞获得性耐药性的HER2抑制剂拉帕替尼。因此，抗性细胞表现出增加的外源FA摄取和代谢可塑性。在体外和体内，CD36的遗传或药理学抑制可抑制拉帕替尼耐药细胞的生长，但不会抑制拉帕替尼敏感细胞的生长。MMTVneu小鼠乳腺组织中Cd 36的缺失显著减弱肿瘤发生。在乳腺癌患者中，抗HER2治疗后CD36表达增加，这与预后不良相关。我们的研究结果将CD36介导的代谢重新连接定义为HER2阳性乳腺癌的一种重要生存机制。
Although it is established that fatty acid (FA) synthesis supports anabolic growth in cancer, the role of exogenous FA uptake remains elusive. Here we show that, during acquisition of resistance to HER2 inhibition, metabolic rewiring of breast cancer cells favors reliance on exogenous FA uptake over de novo FA synthesis. Through cDNA microarray analysis, we identify the FA transporter CD36 as a critical gene upregulated in cells with acquired resistance to the HER2 inhibitor lapatinib. Accordingly, resistant cells exhibit increased exogenous FA uptake and metabolic plasticity. Genetic or pharmacological inhibition of CD36 suppresses the growth of lapatinib-resistant but not lapatinib-sensitive cells in vitro and in vivo. Deletion of Cd36 in mammary tissues of MMTVneu mice significantly attenuates tumorigenesis. In breast cancer patients, CD36 expression increases following anti-HER2 therapy, which correlates with a poor prognosis. Our results define CD36-mediated metabolic rewiring as an essential survival mechanism in HER2-positive breast cancer.