Integrated Pharmacodynamic Analysis Identifies Two Metabolic Adaption Pathways to Metformin in Breast Cancer.
Integrated Pharmacodynamic Analysis Identifies Two Metabolic Adaption Pathways to Metformin in Breast Cancer.
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DOI：
10.1016/j.cmet.2018.08.021
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发表时间：
2018-11-06
期刊：
影响因子：
29
通讯作者：
Harris AL
中科院分区：
文献类型：
--
作者：
Lord SR;Cheng WC;Liu D;Gaude E;Haider S;Metcalf T;Patel N;Teoh EJ;Gleeson F;Bradley K;Wigfield S;Zois C;McGowan DR;Ah-See ML;Thompson AM;Sharma A;Bidaut L;Pollak M;Roy PG;Karpe F;James T;English R;Adams RF;Campo L;Ayers L;Snell C;Roxanis I;Frezza C;Fenwick JD;Buffa FM;Harris AL
二甲双胍作为癌症治疗的后期临床试验正在进行中。然而，二甲双胍在临床剂量下对肿瘤的作用方式仍存在争议。我们进行了一项临床研究，在配对时间点整合全身代谢标志物、动态FDG-PET-CT、转录组学和代谢组学的测量，以分析二甲双胍在原发性乳腺癌中的生物活性。我们发现二甲双胍降低了线粒体代谢物的水平，激活了多种线粒体代谢途径，并增加了肿瘤中的18-FDG通量。两个肿瘤组被鉴定为具有不同的代谢反应，OXPHOS转录反应（OTR）组，其存在OXPHOS基因转录的增加，以及FDG反应组，其具有增加的18-FDG摄取。通过经验证的增殖特征测量的增殖增加表明，OTR组患者对二甲双胍治疗耐药。我们的结论是，线粒体对二甲双胍在原发性乳腺癌中的反应可以定义抗肿瘤作用。二甲双胍在乳腺癌患者中的药效学窗口研究二甲双胍增加原发性乳腺癌中的18-FDG通量在肿瘤中鉴定出对二甲双胍的两种不同代谢反应上调OXPHOS基因的肿瘤显示增殖评分增加使用动态PET成像、代谢组学和转录组学在乳腺癌患者中，Lord et al.发现二甲双胍增加18-FDG流入肿瘤并激活线粒体代谢基因。观察到两种不同的代谢反应，并与不同的增殖特征相关，表明OXPHOS的反应性增加与二甲双胍耐药性相关。
Late-phase clinical trials investigating metformin as a cancer therapy are underway. However, there remains controversy as to the mode of action of metformin in tumors at clinical doses. We conducted a clinical study integrating measurement of markers of systemic metabolism, dynamic FDG-PET-CT, transcriptomics, and metabolomics at paired time points to profile the bioactivity of metformin in primary breast cancer. We show metformin reduces the levels of mitochondrial metabolites, activates multiple mitochondrial metabolic pathways, and increases 18-FDG flux in tumors. Two tumor groups are identified with distinct metabolic responses, an OXPHOS transcriptional response (OTR) group for which there is an increase in OXPHOS gene transcription and an FDG response group with increased 18-FDG uptake. Increase in proliferation, as measured by a validated proliferation signature, suggested that patients in the OTR group were resistant to metformin treatment. We conclude that mitochondrial response to metformin in primary breast cancer may define anti-tumor effect. A pharmacodynamic window study of metformin in patients with breast cancer Metformin increases 18-FDG flux in primary breast cancer Two distinct metabolic responses to metformin are identified in tumors Tumors that upregulate OXPHOS genes show an increase in proliferation score Using dynamic PET imaging, metabolomics, and transcriptomics in breast cancer patients, Lord et al. find that metformin increases 18-FDG flux into tumors and activates mitochondrial metabolism genes. Two distinct metabolic responses are observed and linked to differing proliferation signatures, suggesting that a reactive increase in OXPHOS is linked to metformin resistance.
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癌细胞对葡萄糖限制和双胍类药物敏感性的代谢决定因素。
影响因子：
64.8
作者：
Birsoy, Kivanc;Possemato, Richard;Lorbeer, Franziska K.;Bayraktar, Erol C.;Thiru, Prathapan;Yucel, Burcu;Wang, Tim;Chen, Walter W.;Clish, Clary B.;Sabatini, David M.
通讯作者：
Sabatini, David M.
影响因子：
29
作者：
Liu X;Romero IL;Litchfield LM;Lengyel E;Locasale JW
通讯作者：
Locasale JW
影响因子：
50.3
作者：
Chae YC;Vaira V;Caino MC;Tang HY;Seo JH;Kossenkov AV;Ottobrini L;Martelli C;Lucignani G;Bertolini I;Locatelli M;Bryant KG;Ghosh JC;Lisanti S;Ku B;Bosari S;Languino LR;Speicher DW;Altieri DC
通讯作者：
Altieri DC
影响因子：
11.1
作者：
Mehta, Shaveta;Hughes, Nick P.;Harris, Adrian L.
通讯作者：
Harris, Adrian L.
影响因子：
3.8
作者：
Niraula, Saroj;Dowling, Ryan J. O.;Goodwin, Pamela J.
通讯作者：
Goodwin, Pamela J.