EGFR signaling through an Akt-SREBP-1-dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy.
EGFR signaling through an Akt-SREBP-1-dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy.
复制标题
DOI：
10.1126/scisignal.2000446
复制
发表时间：
2009-12-15
影响因子：
7.3
通讯作者：
Mischel PS
中科院分区：
文献类型：
--
作者：
Guo D;Prins RM;Dang J;Kuga D;Iwanami A;Soto H;Lin KY;Huang TT;Akhavan D;Hock MB;Zhu S;Kofman AA;Bensinger SJ;Yong WH;Vinters HV;Horvath S;Watson AD;Kuhn JG;Robins HI;Mehta MP;Wen PY;DeAngelis LM;Prados MD;Mellinghoff IK;Cloughesy TF;Mischel PS
胶质母细胞瘤是最常见的恶性脑肿瘤，是最致命和最难治疗的癌症之一。虽然表皮生长因子受体（EGFR）突变在胶质母细胞瘤中很常见，但其临床意义知之甚少。对接受EGFR抑制剂拉帕替尼治疗的患者的肿瘤研究显示，EGFR诱导脂肪酸合成的主要转录调节因子固醇调节元件结合蛋白1（SREBP-1）的裂解和核转位。这种反应是由Akt介导的;然而，雷帕霉素治疗患者的临床数据显示，SREBP-1的激活不依赖于雷帕霉素复合物1（mTORC 1）的哺乳动物靶点，这可能解释了雷帕霉素在治疗此类肿瘤中的不良疗效。没有组成型活性EGFR信号传导的胶质母细胞瘤对脂肪酸合成的抑制具有抗性，而引入EGFR的组成型活性突变形式EGFRvIII使小鼠中的肿瘤异种移植物致敏细胞死亡，这通过羟甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂阿托伐他汀增强。这些结果确定了以前未描述的EGFR介导的促生存代谢途径，并提出了治疗EGFR激活的胶质母细胞瘤的新治疗方法。
Glioblastoma, the most common malignant brain tumor, is among the most lethal and difficult cancers to treat. Although epidermal growth factor receptor (EGFR) mutations are frequent in glioblastoma, their clinical relevance is poorly understood. Studies of tumors from patients treated with the EGFR-inhibitor lapatinib revealed that EGFR induces the cleavage and nuclear translocation of the master transcriptional regulator of fatty acid synthesis, sterol regulatory element-binding protein 1 (SREBP-1). This response was mediated by Akt; however, clinical data from rapamycin-treated patients showed that SREBP-1 activation was independent of the mammalian target of rapamycin complex 1 (mTORC1), possibly explaining rapamycin’s poor efficacy in the treatment of such tumors. Glioblastomas without constitutively active EGFR signaling were resistant to inhibition of fatty acid synthesis, whereas introduction of a constitutively active mutant form of EGFR, EGFRvIII, sensitized tumor xenografts in mice to cell death, which was augmented by the hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor atorvastatin. These results identify a previously undescribed EGFR-mediated pro-survival metabolic pathway, and suggest new therapeutic approaches to treating EGFR-activated glioblastomas.
登录
查看更多内容
影响因子：
3.7
作者：
Kong A;Calleja V;Leboucher P;Harris A;Parker PJ;Larijani B
通讯作者：
Larijani B
雷帕霉素在I期试验中针对复发性PTEN缺陷型胶质母细胞瘤患者的抗肿瘤活性。
影响因子：
15.8
作者：
Cloughesy, Tim F.;Yoshimoto, Koji;Nghiemphu, Phioanh;Brown, Kevin;Dang, Julie;Zhu, Shaojun;Hsueh, Teli;Chen, Yinan;Wang, Wei;Youngkin, David;Liau, Linda;Martin, Neil;Becker, Don;Bergsneider, Marvin;Lai, Albert;Green, Richard;Oglesby, Tom;Koleto, Michael;Trent, Jeff;Horvath, Steve;Mischel, Paul S.;Mellinghoff, Ingo K.;Sawyers, Charles L.
通讯作者：
Sawyers, Charles L.
影响因子：
10.3
作者：
Haas-Kogan, DA;Prados, MD;Stokoe, D
通讯作者：
Stokoe, D
影响因子：
64.8
作者：
Chin, L.;Meyerson, M.;Aldape, K.;Bigner, D.;Mikkelsen, T.;VandenBerg, S.;Kahn, A.;Penny, R.;Ferguson, M. L.;Gerhard, D. S.;Getz, G.;Brennan, C.;Taylor, B. S.;Winckler, W.;Park, P.;Ladanyi, M.;Hoadley, K. A.;Verhaak, R. G. W.;Hayes, D. N.;Spellman, Paul T.;Absher, D.;Weir, B. A.;Ding, L.;Wheeler, D.;Lawrence, M. S.;Cibulskis, K.;Mardis, E.;Zhang, Jinghui;Wilson, R. K.;Donehower, L.;Wheeler, D. A.;Purdom, E.;Wallis, J.;Laird, P. W.;Herman, J. G.;Schuebel, K. E.;Weisenberger, D. J.;Baylin, S. B.;Schultz, N.;Yao, Jun;Wiedemeyer, R.;Weinstein, J.;Sander, C.;Gibbs, R. A.;Gray, J.;Kucherlapati, R.;Lander, E. S.;Myers, R. M.;Perou, C. M.;McLendon, Roger;Friedman, Allan;Van Meir, Erwin G;Brat, Daniel J;Mastrogianakis, Gena Marie;Olson, Jeffrey J;Lehman, Norman;Yung, W. K. Alfred;Bogler, Oliver;Berger, Mitchel;Prados, Michael;Muzny, Donna;Morgan, Margaret;Scherer, Steve;Sabo, Aniko;Nazareth, Lynn;Lewis, Lora;Hall, Otis;Zhu, Yiming;Ren, Yanru;Alvi, Omar;Yao, Jiqiang;Hawes, Alicia;Jhangiani, Shalini;Fowler, Gerald;San Lucas, Anthony;Kovar, Christie;Cree, Andrew;Dinh, Huyen;Santibanez, Jireh;Joshi, Vandita;Gonzalez-Garay, Manuel L.;Miller, Christopher A.;Milosavljevic, Aleksandar;Sougnez, Carrie;Fennell, Tim;Mahan, Scott;Wilkinson, Jane;Ziaugra, Liuda;Onofrio, Robert;Bloom, Toby;Nicol, Rob;Ardlie, Kristin;Baldwin, Jennifer;Gabriel, Stacey;Fulton, Robert S.;McLellan, Michael D.;Larson, David E.;Shi, Xiaoqi;Abbott, Rachel;Fulton, Lucinda;Chen, Ken;Koboldt, Daniel C.;Wendl, Michael C.;Meyer, Rick;Tang, Yuzhu;Lin, Ling;Osborne, John R.;Dunford-Shore, Brian H.;Miner, Tracie L.;Delehaunty, Kim;Markovic, Chris;Swift, Gary;Courtney, William;Pohl, Craig;Abbott, Scott;Hawkins, Amy;Leong, Shin;Haipek, Carrie;Schmidt, Heather;Wiechert, Maddy;Vickery, Tammi;Scott, Sacha;Dooling, David J.;Chinwalla, Asif;Weinstock, George M.;O'Kelly, Michael;Robinson, Jim;Alexe, Gabriele;Beroukhim, Rameen;Carter, Scott;Chiang, Derek;Gould, Josh;Gupta, Supriya;Korn, Josh;Mermel, Craig;Mesirov, Jill;Monti, Stefano;Nguyen, Huy;Parkin, Melissa;Reich, Michael;Stransky, Nicolas;Garraway, Levi;Golub, Todd;Protopopov, Alexei;Perna, Ilana;Aronson, Sandy;Sathiamoorthy, Narayan;Ren, Georgia;Kim, Hyunsoo;Kong, Sek Won;Xiao, Yonghong;Kohane, Isaac S.;Seidman, Jon;Cope, Leslie;Pan, Fei;Van Den Berg, David;Van Neste, Leander;Yi, Joo Mi;Li, Jun Z.;Southwick, Audrey;Brady, Shannon;Aggarwal, Amita;Chung, Tisha;Sherlock, Gavin;Brooks, James D.;Jakkula, Lakshmi R.;Lapuk, Anna V.;Marr, Henry;Dorton, Shannon;Choi, Yoon Gi;Han, Ju;Ray, Amrita;Wang, Victoria;Durinck, Steffen;Robinson, Mark;Wang, Nicholas J.;Vranizan, Karen;Peng, Vivian;Van Name, Eric;Fontenay, Gerald V.;Ngai, John;Conboy, John G.;Parvin, Bahram;Feiler, Heidi S.;Speed, Terence P.;Socci, Nicholas D.;Olshen, Adam;Lash, Alex;Reva, Boris;Antipin, Yevgeniy;Stukalov, Alexey;Gross, Benjamin;Cerami, Ethan;Wang, Wei Qing;Qin, Li-Xuan;Seshan, Venkatraman E.;Villafania, Liliana;Cavatore, Magali;Borsu, Laetitia;Viale, Agnes;Gerald, William;Topal, Michael D.;Qi, Yuan;Balu, Sai;Shi, Yan;Wu, George;Bittner, Michael;Shelton, Troy;Lenkiewicz, Elizabeth;Morris, Scott;Beasley, Debbie;Sanders, Sheri;Sfeir, Robert;Chen, Jessica;Nassau, David;Feng, Larry;Hickey, Erin;Schaefer, Carl;Madhavan, Subha;Buetow, Ken;Barker, Anna;Vockley, Joseph;Compton, Carolyn;Vaught, Jim;Fielding, Peter;Collins, Francis;Good, Peter;Guyer, Mark;Ozenberger, Brad;Peterson, Jane;Thomson, Elizabeth
通讯作者：
Thomson, Elizabeth
影响因子：
7.5
作者：
Bublil, Erez M.;Yarden, Yosef
通讯作者：
Yarden, Yosef