Targeting the Vulnerability of Glutathione Metabolism in ARID1A-Deficient Cancers

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

doi:10.1016/j.ccell.2018.12.009

Cited by 211 publications

(176 citation statements)

References 33 publications

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“…A recent prospective cohort study in the USA revealed that only 11% of patients receiving the MSK‐IMPACT gene panel test were subsequently enrolled on genomically matched clinical trials . The gaps between the number of patients with actionable mutations and those receiving genomically matched therapy indicate the need to develop drugs targeting new genes covering not only druggable kinase genes but also nonkinase genes such as epigenomic and transcriptional regulator genes, which are often mutated in a variety of tumors . Developing drugs that target such currently undruggable molecules will be of great help.…”

Section: Discussionmentioning

confidence: 99%

Feasibility and utility of a panel testing for 114 cancer‐associated genes in a clinical setting: A hospital‐based study

Ichikawa²,

et al. 2019

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Next‐generation sequencing ( NGS ) of tumor tissue (ie, clinical sequencing) can guide clinical management by providing information about actionable gene aberrations that have diagnostic and therapeutic significance. Here, we undertook a hospital‐based prospective study ( TOP ‐ GEAR project, 2nd stage) to investigate the feasibility and utility of NGS ‐based analysis of 114 cancer‐associated genes (the NCC Oncopanel test). We examined 230 cases (comprising more than 30 tumor types) of advanced solid tumors, all of which were matched with nontumor samples. Gene profiling data were obtained for 187 cases (81.3%), 111 (59.4%) of which harbored actionable gene aberrations according to the Clinical Practice Guidelines for Next Generation Sequencing in Cancer Diagnosis and Treatment (Edition 1.0) issued by 3 major Japanese cancer‐related societies. Twenty‐five (13.3%) cases have since received molecular‐targeted therapy according to their gene aberrations. These results indicate the utility of tumor‐profiling multiplex gene panel testing in a clinical setting in Japan. This study is registered with UMIN Clinical Trials Registry ( UMIN 000011141).

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Section: Discussionmentioning

confidence: 99%

Feasibility and utility of a panel testing for 114 cancer‐associated genes in a clinical setting: A hospital‐based study

Ichikawa²,

et al. 2019

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“…In addition, ROS could contribute to cancer transformation by promoting gene mutation or by stimulating cellular signaling . The basal level of ROS increases as a result of a decrease of GSH in ARID1A‐deficient ovarian cancer cells . These findings suggest that ARID1A abrogation is involved in oncogenesis by contributing to a dysregulated balance between ROS and GSH homeostasis.…”

Section: Resultsmentioning

confidence: 97%

“…Thus, the balance between oxidative stress and the antioxidant metabolite GSH maintains cellular homeostasis. We recently showed that impairment of the GSH metabolic pathway is a vulnerability of ARID1A‐deficient cancer cells . Glutathione is a tripeptide metabolite synthesized from cysteine, glutamate, and glycine.…”

Section: Synthetic Lethal Targets Based On Targeting the Function Ofmentioning

confidence: 99%

“…Glutathione is a tripeptide metabolite synthesized from cysteine, glutamate, and glycine. ARID1A positively regulates the transcription of SLC7A11, which encodes a protein required for the maintenance of intracellular cysteine . Deficiency in ARID1A results in SLC7A11 downregulation, which decreases intracellular cysteine.…”

Section: Synthetic Lethal Targets Based On Targeting the Function Ofmentioning

confidence: 99%

“…We recently showed that impairment of the GSH metabolic pathway is a vulnerability of ARID1A-deficient cancer cells. 49 Glutathione is a tripeptide metabolite synthesized from cysteine, glutamate, and glycine. ARID1A positively regulates the transcription of SLC7A11, which encodes a protein required for the maintenance of intracellular cysteine.…”

Section: Synthe Ti C Le Thal Targ E Ts Ba S Ed On Targ E Ting the Fmentioning

confidence: 99%

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Synthetic lethal therapy based on targeting the vulnerability of SWI/SNF chromatin remodeling complex‐deficient cancers

Sasaki

Ogiwara

2020

Cancer Science

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The SWI/SNF chromatin remodeling complex is composed of approximately 15 subunits, and approximately 20% of all cancers carry mutations in the genes encoding these subunits. Most of the genetic alterations in these genes are loss‐of‐function mutations. The identification of vulnerability based on synthetic lethality in cancers with SWI/SNF chromatin remodeling complex deficiency contributes to precision medicine. The SWI/SNF chromatin remodeling complex is involved in transcription, DNA repair, DNA replication, and chromosomal segregation. Cancers with deficiency in the SWI/SNF chromatin remodeling complex show increased vulnerability derived from the loss of these functions. Synthetic lethal targets have been identified based on vulnerabilities in the functions of the SWI/SNF chromatin remodeling complex. In this review article, we propose a precision medicine strategy using chemotherapeutic methods, such as molecular targeted therapy and immunotherapy, based on harnessing synthetic lethality in cancers with deficiency in the SWI/SNF chromatin remodeling complex.

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Cysteine is a limiting factor for glioma proliferation and survival

et al. 2022

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Nutritional intervention is becoming more prevalent as adjuvant therapy for many cancers in view of the tumor dependence on external sources for some nutrients. However, little is known about the mechanisms that make cancer cells require certain nutrients from the microenvironment. Herein, we report the dependence of glioma cells on exogenous cysteine/cystine, despite this amino acid being nonessential. Using several 13C‐tracers and analysis of cystathionine synthase and cystathioninase levels, we revealed that glioma cells were not able to support glutathione synthesis through the transsulfuration pathway, which allows methionine to be converted to cysteine in cysteine/cystine‐deprived conditions. Therefore, we explored the nutritional deprivation in a mouse model of glioma. Animals subjected to a cysteine/cystine‐free diet survived longer, although this increase did not attain statistical significance, with concomitant reductions in plasma glutathione and cysteine levels. At the end point, however, tumors displayed the ability to synthesize glutathione, even though higher levels of oxidative stress were detected. We observed a compensation from the nutritional intervention revealed as the recovery of cysteine‐related metabolite levels in plasma. Our study highlights a time window where cysteine deprivation can be exploited for additional therapeutic strategies.

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Targeting the Vulnerability of Glutathione Metabolism in ARID1A-Deficient Cancers

Cited by 211 publications

References 33 publications

Feasibility and utility of a panel testing for 114 cancer‐associated genes in a clinical setting: A hospital‐based study

Feasibility and utility of a panel testing for 114 cancer‐associated genes in a clinical setting: A hospital‐based study

Synthetic lethal therapy based on targeting the vulnerability of SWI/SNF chromatin remodeling complex‐deficient cancers

Cysteine is a limiting factor for glioma proliferation and survival

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