靶向SLC7A11介导的半胱氨酸代谢用于治疗曲妥珠单抗耐药的HER2阳性乳腺癌。

Targeting SLC7A11-mediated cysteine metabolism for the treatment of trastuzumab-resistant HER2-positive breast cancer.

作者信息

Hua Yijia, Duan Ningjun, Sun Chunxiao, Yang Fan, Tian Min, Sun Yanting, Zhao Shuhan, Gong Jue, Liu Qian, Huang Xiang, Liang Yan, Fu Ziyi, Li Wei, Yin Yongmei

机构信息

Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

Gusu School, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China.

出版信息

Elife. 2025 Jun 4;14:RP103953. doi: 10.7554/eLife.103953.

DOI:10.7554/eLife.103953

PMID:40464376

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12136593/

Abstract

Trastuzumab resistance remains a challenge for HER2-positive breast cancer treatment. Targeting metabolic reprogramming would provide novel insights for therapeutic strategies. Here, we integrated metabolomics, transcriptomics, and epigenomics data of trastuzumab-sensitive and primary-resistant HER2-positive breast cancer to identify metabolic alterations. Aberrant cysteine metabolism was discovered in trastuzumab primary-resistant breast cancer at both circulating and intracellular levels. The inhibition of SLC7A11 and cysteine starvation could synergize with trastuzumab to induce ferroptosis. Mechanistically, increased H3K4me3 and decreased DNA methylation enhanced SLC7A11 transcription and cystine uptake in trastuzumab-resistant breast cancer. The regulation of epigenetic modifications modulated cysteine metabolism and ferroptosis sensitivity. These results revealed an innovative approach for overcoming trastuzumab resistance by targeting specific amino acid metabolism.

摘要

曲妥珠单抗耐药仍然是HER2阳性乳腺癌治疗面临的一项挑战。靶向代谢重编程可为治疗策略提供新的见解。在此，我们整合了曲妥珠单抗敏感和原发耐药的HER2阳性乳腺癌的代谢组学、转录组学和表观基因组学数据，以识别代谢改变。在曲妥珠单抗原发耐药乳腺癌的循环和细胞内水平均发现了异常的半胱氨酸代谢。抑制溶质载体家族7成员11（SLC7A11）和半胱氨酸饥饿可与曲妥珠单抗协同诱导铁死亡。从机制上讲，组蛋白H3赖氨酸4三甲基化（H3K4me3）增加和DNA甲基化减少增强了曲妥珠单抗耐药乳腺癌中SLC7A11的转录和胱氨酸摄取。表观遗传修饰的调控调节了半胱氨酸代谢和铁死亡敏感性。这些结果揭示了一种通过靶向特定氨基酸代谢来克服曲妥珠单抗耐药的创新方法。