Supplementary Table S2 from BRCA1-Mediated Dual Regulation of Ferroptosis Exposes a Vulnerability to GPX4 and PARP Co-Inhibition in BRCA1-Deficient Cancers

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posted on 2024-08-02, 07:20 authored by 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

Supplementary table S2 shows relevant gene mutation information for the cell lines and xenografts

Funding

Cancer Prevention and Research Institute of Texas (CPRIT)

National Institutes of Health (NIH)

National Science and Technology Council (NSTC)

Research Center Program from the Ministry of Education in Taiwan

T-STAR Center

U.S. Department of Defense (DOD)

V Foundation

Boot Walk Seed Award from Radiation Oncology Strategic Initiatives at The University of Texas MD Anderson Cancer Center

Institutional Research Fund and Bridge Fund from The University of Texas MD Anderson Cancer Center

The N.G. and Helen T. Hawkins Distinguished Professorship for Cancer Research of MD Anderson Cancer Center

CPRIT Research Training Award CPRIT Training Program

History

ARTICLE 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 patients with BRCA1-mutant breast cancer 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.Significance:BRCA1 deficiency promotes resistance to erastin-induced ferroptosis via blocking VDAC3 yet renders cancer cells vulnerable to GPX4i-induced ferroptosis via inhibiting GPX4. NCOA4 induction and defective GPX4 further synergizes GPX4i with PARPi to induce ferroptosis in BRCA1-deficient cancers and targeting GPX4 mitigates PARPi resistance in those cancers.See related commentary by Alborzinia and Friedmann Angeli, p. 1372

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Keywords

Cell Death And Senescence Ferroptosis Drug Mechanisms Oncogenes & Tumor Suppressors BRCA family

Licence

CC BY