Elevated RET expression enhances EGFR activation and mediates EGFR inhibitor resistance in head and neck squamous cell carcinoma.
Elevated RET expression enhances EGFR activation and mediates EGFR inhibitor resistance in head and neck squamous cell carcinoma.
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RET 表达升高可增强 EGFR 激活并介导头颈鳞状细胞癌中 EGFR 抑制剂耐药性。
DOI：
10.1016/j.canlet.2016.04.023
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发表时间：
2016-07
期刊：
影响因子：
--
通讯作者：
Ji Tong
中科院分区：
文献类型：
--
作者：
Lin Chengzhong;Lu Wei;Ren Zhenhu;Tang Yu;Zhang Chunye;Yang Rong;Chen Yiming;Cao Wei;Wang Lizhen;Wang Xu;Ji Tong
背景与目的：EGFR被替代性受体酪氨酸激酶（RTK）共激活可能介导头颈部鳞状细胞癌（HNSCC）对EGFR抑制剂的耐药性。方法采用免疫组化、western blot、细胞迁移和侵袭试验、细胞增殖、细胞周期分析和体内移植试验等方法，研究RET对HNSCC细胞的作用。结果在HNSCC中观察到高水平的a重排转染（RET），高水平的RET与肿瘤大小的增加相关，晚期肿瘤和降低的总生存率。RET基因敲低可抑制HNSCC细胞的增殖和侵袭。RET表达的抑制显著降低EGFR磷酸化和下游EGFR信号传导。RET信号的抑制显着增加了敏感性的HNSCC细胞EGFR抑制剂厄洛替尼在bothin vitroandin vivomodels.ConclusionOur结果提供了一个临床前的概念验证支持RET信号抑制的作用，在有针对性的治疗方法，以提高疗效的EGFR抑制HNSCC。
Background and aimCo-activation of EGFR by alternative receptor tyrosine kinases (RTKs) might mediate resistance to EGFR inhibition in head and neck squamous cell carcinoma (HNSCC). Here we found a novel mechanism to improve the efficacy of EGFR inhibitor erlotinib on HNSCC.MethodImmunohistochemistry, western blot, cell migration and invasion assays, cell proliferation, cell cycle analysis andin vivoserial transplantation assays were used to evaluate the role of RET on HNSCC cells.ResultsThe elevated levels of a rearranged during transfection (RET) are observed in HNSCC and that high levels of RET correlate with increased tumor size, advanced tumor stage and decreased overall survival rate. The HNSCC cell proliferation and invasion were inhibited by RET knockdownin vitroandin vivo. The inhibition of RET expression markedly reduced EGFR phosphorylation and downstream EGFR signaling. The inhibition of RET signaling significantly increased the sensitivity of HNSCC cells to the EGFR inhibitor erlotinib in bothin vitroandin vivomodels.ConclusionOur results offer a preclinical proof-of-concept supporting a role for RET signaling inhibition in a targeted therapeutic approach to improve the efficacy of EGFR inhibition in HNSCC.
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影响因子：
64.5
作者：
Bonanomi D;Chivatakarn O;Bai G;Abdesselem H;Lettieri K;Marquardt T;Pierchala BA;Pfaff SL
通讯作者：
Pfaff SL
DOI：
10.1158/1078-0432.ccr-12-1555
发表时间：
2013-01-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Stabile LP;He G;Lui VW;Thomas S;Henry C;Gubish CT;Joyce S;Quesnelle KM;Siegfried JM;Grandis JR
通讯作者：
Grandis JR
影响因子：
28.2
作者：
Bardelli A;Corso S;Bertotti A;Hobor S;Valtorta E;Siravegna G;Sartore-Bianchi A;Scala E;Cassingena A;Zecchin D;Apicella M;Migliardi G;Galimi F;Lauricella C;Zanon C;Perera T;Veronese S;Corti G;Amatu A;Gambacorta M;Diaz LA Jr;Sausen M;Velculescu VE;Comoglio P;Trusolino L;Di Nicolantonio F;Giordano S;Siena S
通讯作者：
Siena S
影响因子：
51.1
作者：
Cohen, Ezra E. W.;Davis, Darren W.;Karrison, Theodore G.;Seiwert, Tanguy Y.;Wong, Stuart J.;Nattam, Sreenivasa;Kozloff, Mark F.;Clark, Joseph I.;Yan, Duen-Hwa;Liu, Wen;Pierce, Carolyn;Dancey, Janet E.;Stenson, Kerstin;Blair, Elizabeth;Dekker, Allison;Vokes, Everett E.
通讯作者：
Vokes, Everett E.
影响因子：
3.7
作者：
Esposito CL;D'Alessio A;de Franciscis V;Cerchia L
通讯作者：
Cerchia L