2. Academic Validation
  3. BRCA1-mediated dual regulation of ferroptosis exposes a vulnerability to GPX4 and PARP co-inhibition in BRCA1-deficient cancers

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

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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