Genotype-dependent efficacy of a dual PI3K/mTOR inhibitor, NVP-BEZ235, and an mTOR inhibitor, RAD001, in endometrial carcinomas.
Genotype-dependent efficacy of a dual PI3K/mTOR inhibitor, NVP-BEZ235, and an mTOR inhibitor, RAD001, in endometrial carcinomas.
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DOI：
10.1371/journal.pone.0037431
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Taketani Y
中科院分区：
文献类型：
--
作者：
Shoji K;Oda K;Kashiyama T;Ikeda Y;Nakagawa S;Sone K;Miyamoto Y;Hiraike H;Tanikawa M;Miyasaka A;Koso T;Matsumoto Y;Wada-Hiraike O;Kawana K;Kuramoto H;McCormick F;Aburatani H;Yano T;Kozuma S;Taketani Y
PI 3 K（磷脂酰肌醇-3-激酶）/mTOR（雷帕霉素的哺乳动物靶蛋白）通路在子宫内膜癌中经常通过各种PI 3 K/AKT激活基因改变而被激活。我们在13个子宫内膜癌细胞系中检测了NVP-BEZ 235--一种PI 3 K/mTOR双重表达载体--和RAD 001--一种mTOR表达载体--的抗肿瘤作用，所有这些细胞系都具有一个或多个PTEN、PIK 3CA和K-Ras的改变。我们还将这些化合物与MAPK通路抑制剂（PD 98059或UO 126）在具有K-Ras改变（突变或扩增）的细胞系中组合。没有K-Ras改变的PTEN突变体细胞系（n = 9）比具有K-Ras改变的细胞系（n = 4）对RAD 001和NVP-BEZ 235两者更敏感。 在敏感细胞系中，NVP-BEZ 235比RAD 001更显著地诱导剂量依赖性生长抑制。NVP-BEZ 235以剂量依赖性方式诱导G1期阻滞。我们在裸鼠中观察了RAD 001和NVP-BEZ 235两者的体内抗肿瘤活性。MEK抑制剂PD 98059或UO 126的存在使K-Ras突变细胞对NVP-BEZ 235敏感。NVP-BEZ 235的强大生长抑制表明双重PI 3 K/mTOR抑制剂是子宫内膜癌的有希望的治疗剂。我们的数据表明，在某些子宫内膜癌中，PTEN和K-Ras的突变状态可能是对NVP-BEZ 235敏感性的有用预测因子。
The PI3K (phosphatidylinositol-3-kinase)/mTOR (mammalian target of rapamycin) pathway is frequently activated in endometrial cancer through various PI3K/AKT-activating genetic alterations. We examined the antitumor effect of NVP-BEZ235—a dual PI3K/mTOR inhibitor—and RAD001—an mTOR inhibitor—in 13 endometrial cancer cell lines, all of which possess one or more alterations in PTEN, PIK3CA, and K-Ras. We also combined these compounds with a MAPK pathway inhibitor (PD98059 or UO126) in cell lines with K-Ras alterations (mutations or amplification). PTEN mutant cell lines without K-Ras alterations (n = 9) were more sensitive to both RAD001 and NVP-BEZ235 than were cell lines with K-Ras alterations (n = 4). Dose-dependent growth suppression was more drastically induced by NVP-BEZ235 than by RAD001 in the sensitive cell lines. G1 arrest was induced by NVP-BEZ235 in a dose-dependent manner. We observed in vivo antitumor activity of both RAD001 and NVP-BEZ235 in nude mice. The presence of a MEK inhibitor, PD98059 or UO126, sensitized the K-Ras mutant cells to NVP-BEZ235. Robust growth suppression by NVP-BEZ235 suggests that a dual PI3K/mTOR inhibitor is a promising therapeutic for endometrial carcinomas. Our data suggest that mutational statuses of PTEN and K-Ras might be useful predictors of sensitivity to NVP-BEZ235 in certain endometrial carcinomas.
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影响因子：
8.8
作者：
Cao, P.;Maira, S-M;Garcia-Echeverria, C.;Hedley, D. W.
通讯作者：
Hedley, D. W.
有效使用 PI3K 和 MEK 抑制剂治疗突变型 Kras G12D 和 PIK3CA H1047R 小鼠肺癌。
影响因子：
82.9
作者：
通讯作者：
--
DOI：
10.1016/j.jsbmb.2007.09.020
发表时间：
2008-02-01
影响因子：
4.1
作者：
Doll, A.;Abal, M.;Reventos, J.
通讯作者：
Reventos, J.
DOI：
10.1158/1078-0432.ccr-09-1314
发表时间：
2010-03-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Houghton PJ
通讯作者：
Houghton PJ
影响因子：
5.7
作者：
Maira, Sauveur-Michel;Stauffer, Frederic;Garcia-Echeverria, Carlos
通讯作者：
Garcia-Echeverria, Carlos