BRCA1-mediated dual regulation of ferroptosis exposes a vulnerability to GPX4 and PARP co-inhibition in BRCA1-deficient cancers

  • Cancer Discov. 2024 Mar 28. doi: 10.1158/2159-8290.CD-23-1220.
Guang Lei  1 ,  Chao Mao  2 ,  Amber D Horbath  3 ,  Yuelong Yan  4 ,  Shirong Cai  5 ,  Jun Yao  4 ,  Yan Jiang  6 ,  Mingchuang Sun  1 ,  Xiaoguang Liu  4 ,  Jun Cheng  1 ,  Zhihao Xu  1 ,  Hyemin Lee  6 ,  Qidong Li  1 ,  Zhengze Lu  1 ,  Li Zhuang  7 ,  Mei-Kuang Chen  6 ,  Anagha Alapati  1 ,  Timothy A Yap  6 ,  Mien-Chie Hung  8 ,  M James You  6 ,  Helen Piwnica-Worms  6 ,  Boyi Gan  4
Affiliations
  • 1. The University of Texas MD Anderson Cancer Center, HOUSTON, United States.
  • 2. The University of Texas MD Anderson Cancer Center, United States.
  • 3. MD Anderson Cancer Center, Houston, Texas, United States.
  • 4. The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.
  • 5. University of Texas MD Anderson Cancer Center, TX.
  • 6. The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
  • 7. The University of Texas MD Anderson Cancer Center, Houston, United States.
  • 8. China Medical University, Taichung, Taiwan.
PMID: 38552003 DOI: 10.1158/2159-8290.CD-23-1220
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.

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