Compensatory metabolic networks in pancreatic cancers upon perturbation of glutamine metabolism.
Compensatory metabolic networks in pancreatic cancers upon perturbation of glutamine metabolism.
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胰腺代谢扰动后胰腺癌中的代偿代谢网络。
DOI：
10.1038/ncomms15965
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发表时间：
2017-07-03
影响因子：
16.6
通讯作者：
Kimmelman AC
中科院分区：
文献类型：
--
作者：
Biancur DE;Paulo JA;Małachowska B;Quiles Del Rey M;Sousa CM;Wang X;Sohn ASW;Chu GC;Gygi SP;Harper JW;Fendler W;Mancias JD;Kimmelman AC
胰腺导管腺癌是一种众所周知的难以治疗的癌症，患者需要新的治疗方法。我们之前已经表明，这些肿瘤改变了代谢要求，使它们高度依赖于许多适应，包括非经典的谷氨酰胺（Gln）代谢途径，并且抑制Gln代谢的下游组分会导致肿瘤生长减少。在这里，我们测试是否最近开发的转氨酶（GLS），它介导的Gln代谢的早期步骤的抑制剂，代表一个可行的治疗策略。我们发现，尽管GLS抑制引起的体外增殖的早期效应显着，胰腺癌细胞具有适应性代谢网络，维持体外和体内增殖。我们使用一个综合的代谢组学和蛋白质组学平台来理解这种适应性反应，从而设计合理的组合方法。我们证明胰腺癌代谢是适应性的，靶向谷氨酰胺代谢结合这些适应性反应可能会为患者带来临床益处。谷氨酰胺酶抑制剂（GLSi）对某些癌症具有有希望的活性。在这里，作者表明GLSi对胰腺癌的多种小鼠模型没有影响，并表征了响应GLSi而激活的代谢途径，其伴随的抑制可能具有治疗效用。
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. Glutaminase inhibition (GLSi) has promising activity against certain cancers. Here, the authors show that GLSi has no effect on multiple mouse models of pancreatic cancer and characterize the metabolic pathways activated in response to GLSi whose concomitant inhibition may have therapeutic utility.
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影响因子：
9.9
作者：
Gaglio, Daniela;Metallo, Christian M.;Chiaradonna, Ferdinando
通讯作者：
Chiaradonna, Ferdinando
影响因子：
5.7
作者：
Gross, Matt I.;Demo, Susan D.;Bennett, Mark K.
通讯作者：
Bennett, Mark K.
影响因子：
64.5
作者：
Chio IIC;Jafarnejad SM;Ponz-Sarvise M;Park Y;Rivera K;Palm W;Wilson J;Sangar V;Hao Y;Öhlund D;Wright K;Filippini D;Lee EJ;Da Silva B;Schoepfer C;Wilkinson JE;Buscaglia JM;DeNicola GM;Tiriac H;Hammell M;Crawford HC;Schmidt EE;Thompson CB;Pappin DJ;Sonenberg N;Tuveson DA
通讯作者：
Tuveson DA
影响因子：
13.8
作者：
Bryant, Kirsten L.;Mancias, Joseph D.;Kimmelman, Alec C.;Der, Channing J.
通讯作者：
Der, Channing J.
影响因子：
5.9
作者：
Chakrabarti G;Moore ZR;Luo X;Ilcheva M;Ali A;Padanad M;Zhou Y;Xie Y;Burma S;Scaglioni PP;Cantley LC;DeBerardinis RJ;Kimmelman AC;Lyssiotis CA;Boothman DA
通讯作者：
Boothman DA