Targeting the Vulnerability of Glutathione Metabolism in ARID1A-Deficient Cancers

Affiliations

¹ Division of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Electronic address: [email protected].
² Division of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Department of Obstetrics and Gynecology, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan.
³ Division of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Molecular Oncology, The Jikei University Graduate School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan.
⁴ Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
⁵ Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Yamagata 997-0052, Japan; Shonai Regional Industry Promotion Center, Tsuruoka, Yamagata 997-0015, Japan.
⁶ Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Yamagata 997-0052, Japan.
⁷ Department of Translational Oncology, Fundamental Innovative Oncology Core Center, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
⁸ Department of Gynecology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
⁹ Department of Obstetrics and Gynecology, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan.
¹⁰ Division of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Molecular Oncology, The Jikei University Graduate School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan. Electronic address: [email protected].

PMID: 30686770
DOI: 10.1016/j.ccell.2018.12.009

Free article

Targeting the Vulnerability of Glutathione Metabolism in ARID1A-Deficient Cancers

Hideaki Ogiwara et al. Cancer Cell. 2019.

Free article

. 2019 Feb 11;35(2):177-190.e8.

doi: 10.1016/j.ccell.2018.12.009. Epub 2019 Jan 24.

Authors

Affiliations

¹ Division of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Electronic address: [email protected].
² Division of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Department of Obstetrics and Gynecology, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan.
³ Division of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Molecular Oncology, The Jikei University Graduate School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan.
⁴ Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
⁵ Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Yamagata 997-0052, Japan; Shonai Regional Industry Promotion Center, Tsuruoka, Yamagata 997-0015, Japan.
⁶ Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Yamagata 997-0052, Japan.
⁷ Department of Translational Oncology, Fundamental Innovative Oncology Core Center, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
⁸ Department of Gynecology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
⁹ Department of Obstetrics and Gynecology, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan.
¹⁰ Division of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Molecular Oncology, The Jikei University Graduate School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan. Electronic address: [email protected].

PMID: 30686770
DOI: 10.1016/j.ccell.2018.12.009

Abstract

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.

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Glutathione Metabolism: An Achilles' Heel of ARID1A-Deficient Tumors.
Gorrini C, Mak TW. Gorrini C, et al. Cancer Cell. 2019 Feb 11;35(2):161-163. doi: 10.1016/j.ccell.2019.01.017. Cancer Cell. 2019. PMID: 30753819

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Targeting the Vulnerability of Glutathione Metabolism in ARID1A-Deficient Cancers

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Targeting the Vulnerability of Glutathione Metabolism in ARID1A-Deficient Cancers

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