The receptor kinase c-MET has emerged as a target for glioblastoma therapy. However, treatment resistance emerges inevitably. Here, we performed global metabolite screening with metabolite set enrichment coupled with transcriptome and gene set enrichment analysis and proteomic screening, and identified substantial reprogramming of tumor metabolism involving oxidative phosphorylation and fatty acid oxidation (FAO) with substantial accumulation of acyl-carnitines accompanied by an increase of PGC1α in response to genetic (shRNA and CRISPR/Cas9) and pharmacologic (crizotinib) inhibition of c-MET. Extracellular flux and carbon tracing analyses (U-13C-glucose, U-13C-glutamine, and U-13C-palmitic acid) demonstrated enhanced oxidative metabolism, which was driven by FAO and supported by increased anaplerosis of glucose carbons. These findings were observed in concert with increased number and fusion of mitochondria and production of reactive oxygen species. Genetic interference with PGC1α rescued this oxidative phenotype driven by c-MET inhibition. Silencing and chromatin immunoprecipitation experiments demonstrated that cAMP response elements binding protein regulates the expression of PGC1α in the context of c-MET inhibition. Interference with both oxidative phosphorylation (metformin, oligomycin) and β-oxidation of fatty acids (etomoxir) enhanced the antitumor efficacy of c-MET inhibition. Synergistic cell death was observed with c-MET inhibition and gamitrinib treatment. In patient-derived xenograft models, combination treatments of crizotinib and etomoxir, and crizotinib and gamitrinib were significantly more efficacious than single treatments and did not induce toxicity. Collectively, we have unraveled the mechanistic underpinnings of c-MET inhibition and identified novel combination therapies that may enhance its therapeutic efficacy. Significance: c-MET inhibition causes profound metabolic reprogramming that can be targeted by drug combination therapies.

中文翻译：

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MET抑制诱导胶质母细胞瘤中PGC1α依赖的代谢重编程。

受体激酶c-MET已成为胶质母细胞瘤治疗的靶标。但是，不可避免地出现治疗抗性。在这里，我们进行了代谢物富集，转录组和基因组富集分析以及蛋白质组学筛选，进行了全局代谢物筛选，并确定了涉及氧化磷酸化和脂肪酸氧化（FAO）的肿瘤代谢的大量重编程，其中大量的酰基肉碱伴随着遗传（shRNA和CRISPR / Cas9）和药理学（克唑替尼）对c-MET的抑制导致PGC1α升高。细胞外通量和碳示踪分析（U-13C-葡萄糖，U-13C-谷氨酰胺和U-13C-棕榈酸）显示出增强的氧化代谢，这是由粮农组织推动的，并受到葡萄糖碳的无节制增加的支持。观察到这些发现与线粒体数目的增加和融合以及活性氧的产生相一致。对PGC1α的遗传干扰挽救了这种由c-MET抑制作用驱动的氧化表型。沉默和染色质免疫沉淀实验表明，在c-MET抑制的情况下，cAMP反应元件结合蛋白调节PGC1α的表达。干扰氧化磷酸化（二甲双胍，寡霉素）和脂肪酸的β-氧化（依托莫司）都增强了c-MET抑制的抗肿瘤功效。用c-MET抑制和加米替尼治疗观察到协同细胞死亡。在患者来源的异种移植模型中，克唑替尼和埃托莫西的联合治疗 crizotinib和gamitrinib的疗效明显优于单药，并且不会引起毒性。总的来说，我们已经阐明了c-MET抑制的机制基础，并确定了可以增强其治疗功效的新型联合疗法。意义：c-MET抑制会引起深刻的代谢重编程，可以通过药物联合疗法来靶向。