LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin.
LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin.
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DOI：
10.1016/j.ccr.2012.12.008
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发表时间：
2013-02-11
期刊：
影响因子：
50.3
通讯作者：
Shaw RJ
中科院分区：
文献类型：
--
作者：
Shackelford DB;Abt E;Gerken L;Vasquez DS;Seki A;Leblanc M;Wei L;Fishbein MC;Czernin J;Mischel PS;Shaw RJ
LKB1（也称为STK11）肿瘤抑制因子在约20%的非小细胞肺癌（NSCLC）中发生突变失活。LKB1是激活能量感知激酶AMPK的主要上游激酶，使LKB1缺陷的细胞无法适当地感知代谢应激。我们测试了代谢药物在非小细胞肺癌中的治疗潜力，并发现phenformin（一种线粒体抑制剂和糖尿病治疗药物二甲双胍的类似物）可以选择性地诱导lkb1缺陷的非小细胞肺癌细胞凋亡。在Kras依赖的NSCLC小鼠模型中进行的治疗试验显示，Kras和Lkb1突变的肿瘤，而不是Kras和p53突变的肿瘤，对phenformin作为单一药物表现出选择性反应，从而延长了生存期。这项研究表明，苯双胍作为一种基于癌症代谢的治疗药物，可以选择性地靶向lkb1缺陷肿瘤。
The LKB1 (also called STK11) tumor suppressor is mutationally inactivated in ~20% of non-small cell lung cancers (NSCLC). LKB1 is the major upstream kinase activating the energy-sensing kinase AMPK, making LKB1-deficient cells unable to appropriately sense metabolic stress. We tested the therapeutic potential of metabolic drugs in NSCLC and identified phenformin, a mitochondrial inhibitor and analog of the diabetes therapeutic metformin, as selectively inducing apoptosis in LKB1-deficient NSCLC cells. Therapeutic trials in Kras-dependent mouse models of NSCLC revealed that tumors with Kras and Lkb1 mutations, but not those with Kras and p53 mutations showed selective response to phenformin as a single agent, resulting in prolonged survival. This study suggests phenformin as a cancer metabolism-based therapeutic to selectively target LKB1-deficient tumors.
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AMP激活的蛋白激酶对ULK1（HATG1）的磷酸化将能量传感连接到线粒体。
DOI：
10.1126/science.1196371
发表时间：
2011-01-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Egan DF;Shackelford DB;Mihaylova MM;Gelino S;Kohnz RA;Mair W;Vasquez DS;Joshi A;Gwinn DM;Taylor R;Asara JM;Fitzpatrick J;Dillin A;Viollet B;Kundu M;Hansen M;Shaw RJ
通讯作者：
Shaw RJ
影响因子：
64.8
作者：
Chen, Zhao;Cheng, Katherine;Walton, Zandra;Wang, Yuchuan;Ebi, Hiromichi;Shimamura, Takeshi;Liu, Yan;Tupper, Tanya;Ouyang, Jing;Li, Jie;Gao, Peng;Woo, Michele S.;Xu, Chunxiao;Yanagita, Masahiko;Altabef, Abigail;Wang, Shumei;Lee, Charles;Nakada, Yuji;Pena, Christopher G.;Sun, Yanping;Franchetti, Yoko;Yao, Catherine;Saur, Amy;Cameron, Michael D.;Nishino, Mizuki;Hayes, D. Neil;Wilkerson, Matthew D.;Roberts, Patrick J.;Lee, Carrie B.;Bardeesy, Nabeel;Butaney, Mohit;Chirieac, Lucian R.;Costa, Daniel B.;Jackman, David;Sharpless, Norman E.;Castrillon, Diego H.;Demetri, George D.;Jaenne, Pasi A.;Pandolfi, Pier Paolo;Cantley, Lewis C.;Kung, Andrew L.;Engelman, Jeffrey A.;Wong, Kwok-Kin
通讯作者：
Wong, Kwok-Kin
影响因子：
8
作者：
Gill RK;Yang SH;Meerzaman D;Mechanic LE;Bowman ED;Jeon HS;Roy Chowdhuri S;Shakoori A;Dracheva T;Hong KM;Fukuoka J;Zhang JH;Harris CC;Jen J
通讯作者：
Jen J
影响因子：
50.3
作者：
Carretero J;Shimamura T;Rikova K;Jackson AL;Wilkerson MD;Borgman CL;Buttarazzi MS;Sanofsky BA;McNamara KL;Brandstetter KA;Walton ZE;Gu TL;Silva JC;Crosby K;Shapiro GI;Maira SM;Ji H;Castrillon DH;Kim CF;García-Echeverría C;Bardeesy N;Sharpless NE;Hayes ND;Kim WY;Engelman JA;Wong KK
通讯作者：
Wong KK
影响因子：
50.3
作者：
Chae YC;Caino MC;Lisanti S;Ghosh JC;Dohi T;Danial NN;Villanueva J;Ferrero S;Vaira V;Santambrogio L;Bosari S;Languino LR;Herlyn M;Altieri DC
通讯作者：
Altieri DC