Targeting glutamine dependence through GLS1 inhibition suppresses ARID1A-inactivated clear cell ovarian carcinoma.

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.

• Authors: Shuai Wu, Takeshi Fukumoto, Jianhuang Lin, Timothy Nacarelli, Yemin Wang, Dionzie Ong, Heng Liu, Nail Fatkhutdinov, Joseph A Zundell, Sergey Karakashev, Wei Zhou, Lauren E Schwartz, Hsin-Yao Tang, Ronny Drapkin, Qin Liu, David G Huntsman, Andrew V Kossenkov, David W Speicher, Zachary T Schug, Chi Van Dang, Rugang Zhang
• Journal: Nature cancer (Nat Cancer) Vol. 2 Issue 2 Pg. 189-200 (02 2021) ISSN: 2662-1347 [Electronic] England
• PMID: 34085048 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• ARID1A protein, human
• Arid1a protein, mouse
• DNA-Binding Proteins
• Immune Checkpoint Inhibitors
• Nuclear Proteins
• Transcription Factors
• Glutamine
• GLS1 protein, mouse
• Glutaminase

Topics

• 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)