胰腺癌与谷氨酰胺代谢
  • 胰腺导管腺癌的代谢需要发生改变,高度依赖于某些适应性改变,如非典型谷氨酰胺(Gln)代谢通路,抑制下游Gln代谢组分导致肿瘤生长抑制;
  • 谷氨酰胺酶(GLS)介导Gln代谢的早期步骤,新研发的GLS抑制剂,抑制GLS导致体外增殖抑制,但胰腺癌细胞有适应性代谢网络,对体内小鼠模型无效;
  • 采用整合的代谢组学和蛋白质组学平台,鉴定出补偿性通路;
  • 胰腺癌细胞代谢是自适应性的,靶向Gln代谢联合抑制其他适应性应答,可望产生临床疗效。
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Compensatory metabolic networks in pancreatic cancers upon perturbation of glutamine metabolism

胰腺癌补偿性代谢网络对谷氨酰胺代谢异常的作用

10.1038/ncomms15965

2017-07-03, Article

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Abstract:收起
Pancreatic ductal adenocarcinoma is a notoriously difficult-to-treat cancer and patients are in need of novel therapies. We have shown previously that these tumours have altered metabolic requirements, making them highly reliant on a number of adaptations including a non-canonical glutamine (Gln) metabolic pathway and that inhibition of downstream components of Gln metabolism leads to a decrease in tumour growth. Here we test whether recently developed inhibitors of glutaminase (GLS), which mediates an early step in Gln metabolism, represent a viable therapeutic strategy. We show that despite marked early effects on in vitro proliferation caused by GLS inhibition, pancreatic cancer cells have adaptive metabolic networks that sustain proliferation in vitro and in vivo. We use an integrated metabolomic and proteomic platform to understand this adaptive response and thereby design rational combinatorial approaches. We demonstrate that pancreatic cancer metabolism is adaptive and that targeting Gln metabolism in combination with these adaptive responses may yield clinical benefits for patients.

First Authors:
Douglas E Biancur,Joseph D Mancias

Correspondence Authors:
Joseph D Mancias,Alec C Kimmelman

All Authors:
Douglas E Biancur,Joao A Paulo,Beata Małachowska,Maria Quiles Del Rey,Cristovão M Sousa,Xiaoxu Wang,Albert S W Sohn,Gerald C Chu,Steven P Gygi,J Wade Harper,Wojciech Fendler,Joseph D Mancias,Alec C Kimmelman

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