EGFR-PI3K-PDK1 pathway regulates YAP signaling in hepatocellular carcinoma: the mechanism and its implications in targeted therapy.
EGFR-PI3K-PDK1 pathway regulates YAP signaling in hepatocellular carcinoma: the mechanism and its implications in targeted therapy.
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EGFR-PI3K-PDK1通路调节肝细胞癌中YAP信号：机制及其在靶向治疗中的意义
DOI：
10.1038/s41419-018-0302-x
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发表时间：
2018-02-15
影响因子：
9
通讯作者：
Bi F
中科院分区：
文献类型：
--
作者：
Xia H;Dai X;Yu H;Zhou S;Fan Z;Wei G;Tang Q;Gong Q;Bi F
表皮生长因子受体(EGFR)通路和Hippo信号在肝细胞癌的发生发展中起重要作用。然而，这两条通路之间的串扰及其在靶向治疗中的意义仍不清楚。我们发现，被激活的EGFR信号可以绕过RhoA，促进河马信号的核心效应蛋白YAP(Yes-Associated Protein)及其下游靶标Cyr61的表达。进一步研究表明，EGFR信号主要通过PI3K-PDK1(磷酸肌醇3-激酶-磷酸肌醇依赖的激酶-1)途径激活YAP，而不是AKT和MAPK途径。而YAP基因敲除对EGFR信号转导几乎没有影响。此外，EGF还能以非YAP依赖的方式促进肝癌细胞的增殖。联合靶向YAP和EGFR信号通路的辛伐他汀和EGFR信号通路抑制剂，包括EGFR酪氨酸激酶抑制剂(TKI)吉非替尼、RAF抑制剂索拉非尼和MEK抑制剂曲美替尼，在肝癌细胞中表现出很强的协同细胞毒作用。因此，EGFR-PI3K-PDK1通路可以激活YAP信号通路，激活的EGFR信号通路可以非依赖于YAP信号途径促进肝癌细胞的生长。联合使用FDA批准的抑制剂来同时靶向YAP和EGFR信号转导，提出了几种有前景的治疗肝癌的方法。
The epidermal growth factor receptor (EGFR) pathway and Hippo signaling play an important role in the carcinogenesis of hepatocellular carcinoma (HCC). However, the crosstalk between these two pathways and its implications in targeted therapy remains unclear. We found that the activated EGFR signaling could bypass RhoA to promote the expression of YAP(Yes-associated protein), the core effector of the Hippo signaling, and its downstream target Cyr61. Further studies indicated that EGFR signaling mainly acted through the PI3K-PDK1 (Phosphoinositide 3-kinase-Phosphoinositide-dependent kinase-1) pathway to activate YAP, but not the AKT and MAPK pathways. While YAP knockdown hardly affected the EGFR signaling. In addition, EGF could promote the proliferation of HCC cells in a YAP-independent manner. Combined targeting of YAP and EGFR signaling by simvastatin and the EGFR signaling inhibitors, including the EGFR tyrosine kinase inhibitor (TKI) gefitinib, the RAF inhibitor sorafenib and the MEK inhibitor trametinib, presented strong synergistic cytotoxicities in HCC cells. Therefore, the EGFR-PI3K-PDK1 pathway could activate the YAP signaling, and the activated EGFR signaling could promote the HCC cell growth in a YAP-independent manner. Combined use of FDA-approved inhibitors to simultaneously target YAP and EGFR signaling presented several promising therapeutic approaches for HCC treatment.
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河马效应子YAP促进了对RAF和MEK靶向的癌症疗法的耐药性。
影响因子：
30.8
作者：
Lin L;Sabnis AJ;Chan E;Olivas V;Cade L;Pazarentzos E;Asthana S;Neel D;Yan JJ;Lu X;Pham L;Wang MM;Karachaliou N;Cao MG;Manzano JL;Ramirez JL;Torres JM;Buttitta F;Rudin CM;Collisson EA;Algazi A;Robinson E;Osman I;Muñoz-Couselo E;Cortes J;Frederick DT;Cooper ZA;McMahon M;Marchetti A;Rosell R;Flaherty KT;Wargo JA;Bivona TG
通讯作者：
Bivona TG
癌基因 YAP1 与结直肠癌患者的不良预后和西妥昔单抗耐药性显着相关。
DOI：
10.1158/1078-0432.ccr-14-1374
发表时间：
2015-01-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Lee KW;Lee SS;Kim SB;Sohn BH;Lee HS;Jang HJ;Park YY;Kopetz S;Kim SS;Oh SC;Lee JS
通讯作者：
Lee JS
影响因子：
13.5
作者：
Fuchs, Bryan C.;Hoshida, Yujin;Fujii, Tsutomu;Wei, Lan;Yamada, Suguru;Lauwers, Gregory Y.;McGinn, Christopher M.;DePeralta, Danielle K.;Chen, Xintong;Kuroda, Toshihiko;Lanuti, Michael;Schmitt, Anthony D.;Gupta, Supriya;Crenshaw, Andrew;Onofrio, Robert;Taylor, Bradley;Winckler, Wendy;Bardeesy, Nabeel;Caravan, Peter;Golub, Todd R.;Tanabe, Kenneth K.
通讯作者：
Tanabe, Kenneth K.
影响因子：
64.5
作者：
Kapoor A;Yao W;Ying H;Hua S;Liewen A;Wang Q;Zhong Y;Wu CJ;Sadanandam A;Hu B;Chang Q;Chu GC;Al-Khalil R;Jiang S;Xia H;Fletcher-Sananikone E;Lim C;Horwitz GI;Viale A;Pettazzoni P;Sanchez N;Wang H;Protopopov A;Zhang J;Heffernan T;Johnson RL;Chin L;Wang YA;Draetta G;DePinho RA
通讯作者：
DePinho RA
影响因子：
64.5
作者：
Dong, Jixin;Feldmann, Georg;Pan, Duojia
通讯作者：
Pan, Duojia