Reference Detail

Ref Type

Journal Article

PMID

(30686770)

Authors

Ogiwara H, Takahashi K, Sasaki M, Kuroda T, Yoshida H, Watanabe R, Maruyama A, Makinoshima H, Chiwaki F, Sasaki H, Kato T, Okamoto A, Kohno T

Title

Targeting the Vulnerability of Glutathione Metabolism in ARID1A-Deficient Cancers.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer cell	35	2	2019 Feb 11	177-190.e8	Cancer Cell

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ARID1A dec exp	ovarian cancer	predicted - sensitive	Buthionine sulfoximine	Preclinical - Cell line xenograft	Actionable	In a preclinical study, ovarian cancer cells with ARID1A-deficiency via knockdown were sensitive to treatment with Buthionine sulfoximine (BSO), demonstrating decreased cell survival and reduced colony formation in culture and tumor growth suppression in cell-line xenograft models (PMID: 30686770).	30686770
ARID1A dec exp	ovarian cancer	predicted - sensitive	APR-246	Preclinical - Cell line xenograft	Actionable	In a preclinical study, ovarian cancer cells with ARID1A-deficiency via knockdown were sensitive to treatment with APR-246, demonstrating decreased cell survival and reduced colony formation in culture and tumor growth suppression in cell-line xenograft models (PMID: 30686770).	30686770