論文 - 詳細
| RRC ID | 72488 |
|---|---|
| 著者 | Wu S, Fukumoto T, Lin J, Nacarelli T, Wang Y, Ong D, Liu H, Fatkhutdinov N, Zundell JA, Karakashev S, Zhou W, Schwartz LE, Tang HY, Drapkin R, Liu Q, Huntsman DG, Kossenkov AV, Speicher DW, Schug ZT, Van Dang C, Zhang R. |
| タイトル | Targeting glutamine dependence through GLS1 inhibition suppresses ARID1A-inactivated clear cell ovarian carcinoma. |
| ジャーナル | Nat Cancer |
| Abstract |
Alterations in components of the SWI/SNF chromatin-remodeling complex occur in ~20% of all human cancers. For example, ARID1A is mutated in up to 62% of clear cell ovarian carcinoma (OCCC), a disease currently lacking effective therapies. Here we show that ARID1A mutation creates a dependence on glutamine metabolism. SWI/SNF represses glutaminase (GLS1) and ARID1A inactivation upregulates GLS1. ARID1A inactivation increases glutamine utilization and metabolism through the tricarboxylic acid cycle to support aspartate synthesis. Indeed, glutaminase inhibitor CB-839 suppresses the growth of ARID1A mutant, but not wildtype, OCCCs in both orthotopic and patient-derived xenografts. In addition, glutaminase inhibitor CB-839 synergizes with immune checkpoint blockade anti-PDL1 antibody in a genetic OCCC mouse model driven by conditional Arid1a inactivation. Our data indicate that pharmacological inhibition of glutaminase alone or in combination with immune checkpoint blockade represents an effective therapeutic strategy for cancers involving alterations in the SWI/SNF complex such as ARID1A mutations. |
| 巻・号 | 2(2) |
| ページ | 189-200 |
| 公開日 | 2021-2-1 |
| DOI | 10.1038/s43018-020-00160-x |
| PII | 10.1038/s43018-020-00160-x |
| PMID | 34085048 |
| PMC | PMC8168620 |
| MeSH | Adenocarcinoma, Clear Cell* / drug therapy Animals DNA-Binding Proteins / genetics Female Glutaminase / genetics Glutamine / therapeutic use Humans Immune Checkpoint Inhibitors Mice Nuclear Proteins / genetics Ovarian Neoplasms* / drug therapy Transcription Factors / genetics |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 40 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | JHOC-5(RCB1520) JHOC-7(RCB1688) JHOC-9(RCB2226) |