Targeting SLC7A11-mediated cysteine metabolism for the treatment of trastuzumab-resistant HER2-positive breast cancer.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 40464376.
- Also identified by DOI 10.7554/eLife.103953 and PMC identifier 12136593.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Trastuzumab
- Breast Neoplasms
- Drug Resistance, Neoplasm
- Erb-b2 Receptor Tyrosine Kinases
- Cysteine
- Amino Acid Transport System y+
- Antineoplastic Agents, Immunological