文章目录

通过GLS1抑制靶向谷氨酰胺依赖抑制arid1a失活透明细胞卵巢癌

原文发布日期：2021-01-11

英文摘要：

摘要翻译：

原文链接：

文章：

通过GLS1抑制靶向谷氨酰胺依赖抑制arid1a失活透明细胞卵巢癌

Targeting glutamine dependence through GLS1 inhibition suppresses ARID1A-inactivated clear cell ovarian carcinoma

原文发布日期：2021-01-11

英文摘要：

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 ovarian clear cell carcinomas (OCCC), a disease 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 wild-type, OCCCs in both orthotopic and patient-derived xenografts. In addition, glutaminase inhibitor CB-839 synergizes with immune checkpoint blockade anti-PD-L1 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.

摘要翻译：

SWI/SNF染色质重塑复合体组成部分的改变在约20%的人类癌症中发生。例如，ARID1A基因突变在卵巢平滑肌癌（OCCC）患者中高达62%，而该病目前缺乏有效治疗方法。我们发现，ARID1A突变导致对氨代谢的依赖。SWI/SNF复合体抑制了谷氨酰胺水解酶(GLS1)，而ARID1A失活则上调了GLS1表达。ARID1A失活增加了对氨的利用和代谢途径，并通过三羧酸循环支持半胱氨酸合成。确实，谷氨酰胺酶抑制剂CB-839抑制了ARID1A突变体癌细胞的增长，但在假人脱氧核苷酸瘤中未见效果。此外，在由条件性抑制ARID1A驱动的基因OCCC小鼠模型中，谷氨酰胺酶抑制剂CB-839与免疫检查点阻断剂联合使用协同作用。我们得出结论：仅通过抑制谷氨酰胺酶或与免疫检查点阻断剂联用，针对涉及SWI/SNF复合体改变的癌症（如ARID1A突变）具有有效治疗策略。