Targeted inhibition of glutamine metabolism enhances the antitumor effect of selumetinib in KRAS-mutant NSCLC.
Targeted inhibition of glutamine metabolism enhances the antitumor effect of selumetinib in KRAS-mutant NSCLC.
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DOI：
10.1016/j.tranon.2020.100920
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发表时间：
2021-01
影响因子：
5
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Xia M;Li X;Diao Y;Du B;Li Y
KRAS突变型NSCLC的谷氨酰胺利用率高于KRAS野生型。靶向GLS 1和MEK抑制增强体外和体内抗肿瘤活性。18F-FDG PET显像可以很好地识别治疗反应。GLS 1和MEK的双重抑制诱导氧化还原和能量应激。GLS 1和MEK的双重抑制抑制AKT的磷酸化。在肿瘤微环境的调节下，肿瘤的代谢网络被重新编程，由癌基因和肿瘤抑制基因驱动。不同组织类型和不同驱动基因的肿瘤的代谢表型是极其异质的。KRAS突变型非小细胞肺癌（NSCLC）具有谷氨酰胺依赖性。在这项研究中，我们证明了KRAS突变型NSCLC的谷氨酰胺利用率高于KRAS野生型。CB 839是一种有效的转氨酶抑制剂，与MEK抑制剂selumetinib协同作用，可增强KRAS突变型NSCLC细胞和异种移植物的抗肿瘤活性，治疗反应可通过18 F-FDG PET成像很好地确定。联合治疗诱导氧化还原应激，表现为线粒体膜电位降低和ROS水平增加，能量应激表现为糖酵解和谷氨酰胺降解的抑制。AKT的磷酸化也受到抑制。这些作用结合起来诱导自噬，从而导致癌细胞死亡。我们的研究结果表明，双重抑制KRAS突变激活的MEK-ERK通路和谷氨酰胺代谢可能是KRAS驱动的NSCLC的有效治疗策略。
The glutamine utilization of KRAS-mutant NSCLC is higher than that of KRAS wild-type. Targeted GLS1 and MEK inhibition enhance antitumor activity in vitro and in vivo. The therapeutic response can be well identified by 18F-FDG PET imaging. Dual inhibition of GLS1 and MEK induce redox and energetic stress. Dual inhibition of GLS1 and MEK suppress the phosphorylation of AKT. Regulated by the tumor microenvironment, the metabolic network of the tumor is reprogrammed, driven by oncogenes and tumor suppressor genes. The metabolic phenotype of tumors of different driven-genes and different tissue types is extremely heterogeneous. KRAS-mutant non-small cell lung cancer (NSCLC) has glutamine dependence. In this study, we demonstrated that glutamine utilization of KRAS-mutant NSCLC was higher than that of KRAS wild-type. CB839, an efficient glutaminase inhibitor, synergized with the MEK inhibitor selumetinib to enhance antitumor activity in KRAS-mutant NSCLC cells and xenografts, and the therapeutic response could be well identified by 18F-FDG PET imaging. Combination therapy induced redox stress, manifesting as a decrease in mitochondrial membrane potential and an increase in ROS levels, and energetic stress manifesting as suppression of glycolysis and glutamine degradation. The phosphorylation of AKT was also suppressed. These effects combined to induce autophagy and thereby caused cancer cell death. Our results suggest that dual inhibition of the MEK-ERK pathway and glutamine metabolism activated by KRAS mutation may be an effective treatment strategy for KRAS-driven NSCLC.
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影响因子：
11.2
作者：
Galan-Cobo, Ana;Sitthideatphaiboon, Piyada;Heymach, John, V
通讯作者：
Heymach, John, V
影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
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作者：
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通讯作者：
Locasale JW
影响因子：
2.6
作者：
Boysen, Gunnar;Jamshidi-Parsian, Azemat;Griffin, Robert J.
通讯作者：
Griffin, Robert J.
影响因子：
5.7
作者：
Gross, Matt I.;Demo, Susan D.;Bennett, Mark K.
通讯作者：
Bennett, Mark K.