BRCA1-Mediated Dual Regulation of Ferroptosis Exposes a Vulnerability to GPX4 and PARP Co-Inhibition in BRCA1-Deficient Cancers

Authors

Guang Lei
Chao Mao
Amber D Horbath
Yuelong Yan
Shirong Cai
Jun Yao
Yan Jiang
Mingchuang Sun
Xiaoguang Liu
Jun Cheng
Zhihao Xu
Hyemin Lee
Qidong Li
Zhengze Lu
Li Zhuang
Mei-Kuang Chen
Anagha Alapati
Timothy A Yap
Mien-Chie Hung
Mingjian James You
Helen Piwnica-Worms
Boyi Gan

Publication Date

8-2-2024

Journal

Cancer Discovery

DOI

10.1158/2159-8290.CD-23-1220

PMID

38552003

PMCID

PMC11296921

PubMedCentral® Posted Date

2-2-2025

PubMedCentral® Full Text Version

Author MSS

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

Published Open-Access

yes

Recommended Citation

Lei, Guang; Mao, Chao; Horbath, Amber D; et al., "BRCA1-Mediated Dual Regulation of Ferroptosis Exposes a Vulnerability to GPX4 and PARP Co-Inhibition in BRCA1-Deficient Cancers" (2024). Faculty, Staff and Student Publications. 3166.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/3166