Targeting the Vulnerability of Glutathione Metabolism in ARID1A-Deficient Cancers

Cancer Cell. 2019 Feb 11;35(2):177-190.e8. doi: 10.1016/j.ccell.2018.12.009. Epub 2019 Jan 24.


ARID1A encodes an SWI/SNF chromatin-remodeling factor and is frequently mutated in various cancers. This study demonstrates that ARID1A-deficient cancer cells are specifically vulnerable to inhibition of the antioxidant glutathione (GSH) and the glutamate-cysteine ligase synthetase catalytic subunit (GCLC), a rate-limiting enzyme for GSH synthesis. Inhibition of GCLC markedly decreased GSH in ARID1A-deficient cancer cells, leading to apoptotic cell death triggered by excessive amounts of reactive oxygen species. The vulnerability of ARID1A-deficient cancer cells results from low basal levels of GSH due to impaired expression of SLC7A11. The SLC7A11-encoded cystine transporter supplies cells with cysteine, a key source of GSH, and its expression is enhanced by ARID1A-mediated chromatin remodeling. Thus, ARID1A-deficient cancers are susceptible to synthetic lethal targeting of GCLC.

Keywords: APR-246; ARID1A; GCLC; SWI/SNF chromatin-remodeling complex; glutathione; ovarian cancer; ovarian clear cell carcinoma; reactive oxygen species; synthetic lethality; vulnerability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport System y+ / genetics
  • Amino Acid Transport System y+ / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • DNA-Binding Proteins
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Glutamate-Cysteine Ligase / antagonists & inhibitors*
  • Glutamate-Cysteine Ligase / metabolism
  • Glutathione / metabolism*
  • HCT116 Cells
  • Humans
  • Mice, Inbred BALB C
  • Mice, Nude
  • Molecular Targeted Therapy
  • Nuclear Proteins / deficiency*
  • Nuclear Proteins / genetics
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Oxidative Stress / drug effects*
  • Quinuclidines / pharmacology*
  • Transcription Factors / deficiency*
  • Transcription Factors / genetics
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • ARID1A protein, human
  • Amino Acid Transport System y+
  • Antineoplastic Agents
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Nuclear Proteins
  • Quinuclidines
  • SLC7A11 protein, human
  • Transcription Factors
  • GCLC protein, human
  • Glutamate-Cysteine Ligase
  • Glutathione
  • eprenetapopt