GLS1 is a Protective Factor in Patients with Ovarian Clear Cell Carcinoma and its Expression Does Not Correlate with ARID1A-mutated Tumors

Targeting glutamine metabolism has emerged as a novel therapeutic strat-eg y for several human cancers, including ovarian cancer. The primary target of this approach is the 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 promis-ing results. The first clinical trial of CB839 in platinum-resistant patients with ovarian cancer is forthcoming. ARIDIA-mutated ovarian clear cell carcinoma (OCCC) is a relatively indolent and chemoresistant ovarian can-cer histotype. In OCCC-derived cells ARID1A simultaneously drives GLS1 expression and metabolism reprograming. In ARID1A-mutated OCCC-derived mouse models, loss of ARID1A corresponds to GLS1 upregulation and increases sensitivity to GLS1 inhibition. Thus, targeting of GLS1 with CB839 has been suggested as a targeted approach for patients with OCCC with tumors harboring ARIDIA mutations. Here, we investigated whether GLS1 is differentially expressed between patients with OCCC whose tumors are ARID1A positive and patients whose tumors are ARID1A negative. In clinical specimens of OCCC, we found that GLS1 overexpression was not correlated with ARID1A loss. In addition, GLS1 overexpression was asso-ciated with better clinical outcomes. Our findings have implications for human trials using experimental therapeutics targeting GLS1. Significance: GLS1 differential expression in patients with OCCC with or without ARID1A mutations is significant because a clinical trial with a GLS1 inhibitor is forthcoming. Tumors without ARID1A have low levels of GLS1 and GLS1 expression is associated to better outcome. Thus, blockade of GLS1 could be counterproductive for patients with OCCC.

Automated summary

Targeting glutamine metabolism has been proposed as a therapeutic strategy for ovarian cancer, and the kidney isoform of glutaminase, GLS1, has emerged as a potential target. CB839, a first-in-class GLS1 inhibitor, has shown promise in clinical trials and is being investigated in platinum-resistant ovarian cancer patients. In OCCC, the presence of ARID1A mutations has been suggested to drive GLS1 expression and metabolism reprogramming. However, our study found that GLS1 overexpression was not correlated with ARID1A loss in clinical specimens of OCCC, and was associated with better clinical outcomes. This suggests that blockade of GLS1 may not be beneficial for OCCC patients.