Faculty, Staff and Student Publications
Publication Date
8-2-2024
Journal
Cancer Discovery
Abstract
Resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) limits the therapeutic efficacy of PARP inhibition in treating breast cancer susceptibility gene 1 (BRCA1)-deficient cancers. Here we reveal that BRCA1 has a dual role in regulating ferroptosis. BRCA1 promotes the transcription of voltage-dependent anion channel 3 (VDAC3) and glutathione peroxidase 4 (GPX4); consequently, BRCA1 deficiency promotes cellular resistance to erastin-induced ferroptosis but sensitizes cancer cells to ferroptosis induced by GPX4 inhibitors (GPX4i). In addition, nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and defective GPX4 induction unleash potent ferroptosis in BRCA1-deficient cancer cells upon PARPi and GPX4i co-treatment. Finally, we show that xenograft tumors derived from BRCA1-mutant breast cancer patients with PARPi resistance exhibit decreased GPX4 expression and high sensitivity to PARP and GPX4 co-inhibition. Our results show that BRCA1 deficiency induces a ferroptosis vulnerability to PARP and GPX4 co-inhibition and inform a therapeutic strategy for overcoming PARPi resistance in BRCA1-deficient cancers.
Keywords
Ferroptosis, Humans, Phospholipid Hydroperoxide Glutathione Peroxidase, Poly(ADP-ribose) Polymerase Inhibitors, BRCA1 Protein, Female, Animals, Mice, Cell Line, Tumor, Breast Neoplasms, Xenograft Model Antitumor Assays, Nuclear Receptor Coactivators, BRCA1, ferroptosis, GPX4, VDAC3, PARP inhibitor, cancer therapy
DOI
10.1158/2159-8290.CD-23-1220
PMID
38552003
PMCID
PMC11296921
PubMedCentral® Posted Date
2-2-2025
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
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Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons