MassIVE MSV000086347

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GNPS - Therapeutic targeting glutamine dependence in SWI/SNF-inactivated cancers

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Description

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 I (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 a novel therapeutic strategy for cancers involving alterations in the SWI/SNF complex such as ARID1A mutations. [doi:10.25345/C53204] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: cancer ; metabolomics

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Principal Investigators:
(in alphabetical order) 		Rugang Zhang, The Wistar Institute, United States
Submitting User: tangh
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GNPS content goes here (MSV000086347 [task=4b7231e7db3b4801a9da21b2bb41d388])
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