Reference - Detail
| RRC ID | 72488 |
|---|---|
| Author | 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. |
| Title | Targeting glutamine dependence through GLS1 inhibition suppresses ARID1A-inactivated clear cell ovarian carcinoma. |
| Journal | 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. |
| Volume | 2(2) |
| Pages | 189-200 |
| Published | 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 |
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 40 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | JHOC-5(RCB1520) JHOC-7(RCB1688) JHOC-9(RCB2226) |