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Targeting the Vulnerability of Glutathione Metabolism in ARID1A-Deficient Cancers

2019; Cell Press; Volume: 35; Issue: 2 Linguagem: Inglês

10.1016/j.ccell.2018.12.009

1878-3686

Hideaki Ogiwara, Kazuaki Takahashi, Mariko Sasaki, Takafumi Kuroda, Hiroshi Yoshida, Reiko Watanabe, Ami Maruyama, Hideki Makinoshima, Fumiko Chiwaki, Hiroki Sasaki, Tomoyasu Kato, Aikou Okamoto, Takashi Kohno,

interferon and immune responses

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.