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Application of AlDeSense to Stratify Ovarian Cancer Cells Based on Aldehyde Dehydrogenase 1A1 Activity
Published on: March 31, 2023
Targeting glutamine dependence through GLS1 inhibition suppresses ARID1A-inactivated clear cell ovarian carcinoma
Shuai Wu1, Takeshi Fukumoto1, Jianhuang Lin1
1Immunology, Microenvironment & Metastasis Program, The Wistar Institute, Philadelphia, PA, USA.
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.
Insights
ARID1A mutations in cancer lead to a reliance on glutamine metabolism. Inhibiting glutaminase shows promise as a targeted therapy for ARID1A-mutant cancers, potentially combined with immunotherapy.
Area of Science:
- Oncology
- Cancer Metabolism
- Chromatin Remodeling
Background:
- Alterations in the SWI/SNF chromatin-remodeling complex are implicated in approximately 20% of human cancers.
- ARID1A mutations are frequent in clear cell ovarian carcinoma (OCCC), a cancer with limited treatment options.
Purpose of the Study:
- To investigate the functional consequences of ARID1A mutations in cancer.
- To identify therapeutic vulnerabilities associated with ARID1A loss.
Main Methods:
- Assessed the role of ARID1A in regulating glutamine metabolism.
- Utilized glutaminase inhibitor CB-839 in preclinical models of OCCC (orthotopic and patient-derived xenografts).
- Evaluated the combination of CB-839 and anti-PDL1 immunotherapy in a genetic OCCC mouse model.
Main Results:
- ARID1A inactivation upregulates glutaminase (GLS1), increasing glutamine metabolism and aspartate synthesis.
- Glutaminase inhibition with CB-839 suppressed the growth of ARID1A-mutant OCCCs.
- CB-839 demonstrated synergistic effects with anti-PDL1 immunotherapy in a relevant OCCC model.
Conclusions:
- ARID1A mutations confer a dependence on glutamine metabolism.
- Targeting glutaminase is a potential therapeutic strategy for ARID1A-mutant cancers.
- Combination therapy with glutaminase inhibitors and immune checkpoint blockade may benefit patients with SWI/SNF-altered cancers.
