GLS1 is a protective factor in patients with ovarian clear cell carcinoma and its expression does not correlate with ARID1A-mutated tumors.
GLS1 is a protective factor in patients with ovarian clear cell carcinoma and its expression does not correlate with ARID1A-mutated tumors.
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DOI：
10.1158/2767-9764.crc-22-0122
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发表时间：
2022-08
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靶向谷氨酰胺代谢已成为包括卵巢癌在内的几种人类癌症的新治疗策略。这种方法的主要靶点是肾脏谷氨酰胺酶亚型谷氨酰胺酶1(GLS1)，这是谷氨酰胺代谢的关键酶，在几种人类癌症中过度表达。一种一流的GLS1抑制剂，称为CB839(Telaglenastat)，已经在几个临床试验中进行了研究，结果令人振奋。CB839在对铂耐药的卵巢癌患者中的首次临床试验即将到来。ARID1A突变的卵巢透明细胞癌(OCCC)是一种相对惰性和化疗耐药的卵巢癌组织类型。在OCCC来源的细胞中，ARID1A同时驱动GLS1的表达和新陈代谢的重新编程。在ARID1A突变的OCCC衍生小鼠模型中，ARID1A的缺失对应于GLS1上调，并增加了对GLS1抑制的敏感性。因此，CB839靶向GLS1已被建议作为具有ARID1A突变的肿瘤患者的OCCC的靶向方法。在这里，我们调查了肿瘤为ARID1A阳性的OCCC患者和肿瘤为ARID1A阴性的患者之间GLS1是否存在差异表达。在OCCC的临床标本中，我们发现GLS1的过度表达与ARID1A缺失无关。此外，GLS1的过度表达与更好的临床结果相关。我们的发现对使用针对GLS1的实验疗法进行人体试验具有指导意义。GLS1在有或没有ARID1A突变的OCCC患者中的差异表达具有重要意义，因为GLS1抑制剂的临床试验即将到来。没有ARID1A的肿瘤GLS1水平较低，GLS1表达与较好的预后相关。因此，阻断GLS1可能会对OCCC患者产生反作用。
Targeting glutamine metabolism has emerged as a novel therapeutic strategy 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 promising results. The first clinical trial of CB839 in platinum-resistant patients with ovarian cancer is forthcoming. ARID1A-mutated ovarian clear cell carcinoma (OCCC) is a relatively indolent and chemoresistant ovarian cancer 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 ARID1A 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 associated with better clinical outcomes. Our findings have implications for human trials using experimental therapeutics targeting GLS1. 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.
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