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

Alterations in components of the SWI/SNF chromatin-remodeling complex occur in similar to 20% of all human cancers. For example, ARID1A is mutated in up to 62% of ovarian clear cell carcinomas (OCCC), a disease 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 wild-type, OCCCs in both orthotopic and patient-derived xenografts. In addition, glutaminase inhibitor CB-839 synergizes with immune checkpoint blockade anti-PD-L1 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.

Automated summary

Mutations in components of the SWI/SNF chromatin remodeling complex, such as ARID1A, lead to a dependence on glutamine metabolism. Inactivation of ARID1A upregulates GLS1, increasing glutamine utilization and metabolism to support aspartate synthesis. Pharmacological inhibition of glutaminase with CB-839 alone or in combination with immune checkpoint blockade shows promise as a therapeutic strategy for cancers with SWI/SNF complex alterations, including ARID1A mutations.