GLS1 is a protective factor rather than a molecular target in ARID1A-mutated ovarian clear cell carcinoma

Abstract

Targeting glutamine metabolism has emerged as a novel therapeutic strategy for several human cancers, including ovarian cancer. The primary target of this approach is kidney isoform of glutaminase (Glutaminase 1, GLS1), a key enzyme in glutamine metabolism that is overexpressed in several human cancers. A first-in-class inhibitor of GLS1, called CB839 (Telaglenastat), has been investigated in several clinical trials, with promising results. The first clinical trial of CB839 in platinum resistant ovarian cancer patients is forthcoming. ARID1A-mutated ovarian clear cell carcinoma (OCCC) is a relatively indolent and also chemoresistant ovarian cancer histotype. In OCCC derived cells in vitro as well in mouse models, loss of ARID1A leads to upregulation of GLS1. Thus, targeting of GLS1 with CB839 has been suggested as a targeted approach for OCCC patients with tumors harboring ARID1A-mutations. Here, we investigated whether GLS1 is differentially expressed between OCCC patients whose tumors are ARID1A positive and patients whose tumors are ARID1A negative. If validated, testing of ARID1A would provide a new time and cost-effective predictive biomarker for stratification of OCCC patients based on the likelihood to respond to CB839 treatment. We found that in clinical specimens of OCCC GLS1 overexpression is not correlated to ARID1A loss; on the contrary, this overexpression is actually associated with better outcome. Our findings suggest that in OCCC, GLS1 may be a protective factor and that caution should be taken when considering the use of CB839 to treat OCCC patients.