Characterization and targeting of phosphatidylinositol-3 kinase (PI3K) and mammalian target of rapamycin (mTOR) in renal cell cancer.
Characterization and targeting of phosphatidylinositol-3 kinase (PI3K) and mammalian target of rapamycin (mTOR) in renal cell cancer.
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DOI：
10.1186/1479-5876-9-133
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发表时间：
2011-08-11
影响因子：
7.4
通讯作者：
Kluger HM
中科院分区：
文献类型：
--
作者：
Elfiky AA;Aziz SA;Conrad PJ;Siddiqui S;Hackl W;Maira M;Robert CL;Kluger HM
PI3K 和 mTOR 是对细胞生存至关重要的信号转导途径的关键组成部分。许多PI3K抑制剂已进入临床试验，而mTOR是已批准治疗转移性肾细胞癌（RCC）药物的靶点。我们对 RCC 标本中 p85 和 p110α PI3K 亚基和 mTOR 的表达进行了表征，并在体外评估了这些分子的药理学共同靶向。我们使用包含 330 个肾切除病例的组织微阵列，使用基于免疫荧光的新型原位蛋白表达自动定量分析 (AQUA) 方法。在 RCC 细胞系中，我们评估了 PI3K 和 mTOR 抑制剂之间的协同作用以及共同靶向 PI3K 和 mTOR 的 NVP-BEZ235 的活性。 p85 表达与高分期和分级相关（两者 P < 0.0001）。高 p85 和高 mTOR 表达与生存率降低密切相关，并且高 p85 在多变量分析中是独立的预后。在人类样本中发现了 PI3K 亚基和 mTOR 的强烈共表达。 PI3K 抑制剂 LY294002 和雷帕霉素在所研究的所有六种 RCC 细胞系中均具有高度协同作用。所有使用的雷帕霉素浓度都观察到类似的协同作用。 NVP-BEZ235 在体外抑制 RCC 细胞生长，IC50 在低 ηM 范围内并导致 PARP 裂解。 RCC 中 PI3K 和 mTOR 的高表达定义了存活率降低的人群，表明它们是 RCC 中良好的药物靶点。这些靶标往往是共同表达的，并且共同靶向这些分子具有协同作用。 NVP-BEZ235 在体外对 RCC 细胞有活性；表明 RCC 中同时 PI3K 和 mTOR 靶向值得进一步研究。
PI3K and mTOR are key components of signal transduction pathways critical for cell survival. Numerous PI3K inhibitors have entered clinical trials, while mTOR is the target of approved drugs for metastatic renal cell carcinoma (RCC). We characterized expression of p85 and p110α PI3K subunits and mTOR in RCC specimens and assessed pharmacologic co-targeting of these molecules in vitro. We employed tissue microarrays containing 330 nephrectomy cases using a novel immunofluorescence-based method of Automated Quantitative Analysis (AQUA) of in situ protein expression. In RCC cell lines we assessed synergism between PI3K and mTOR inhibitors and activity of NVP-BEZ235, which co-targets PI3K and mTOR. p85 expression was associated with high stage and grade (P < 0.0001 for both). High p85 and high mTOR expression were strongly associated with decreased survival, and high p85 was independently prognostic on multi-variable analysis. Strong co-expression of both PI3K subunits and mTOR was found in the human specimens. The PI3K inhibitor LY294002 and rapamycin were highly synergistic in all six RCC cell lines studied. Similar synergism was seen with all rapamycin concentrations used. NVP-BEZ235 inhibited RCC cell growth in vitro with IC50s in the low ηM range and resultant PARP cleavage. High PI3K and mTOR expression in RCC defines populations with decreased survival, suggesting that they are good drug targets in RCC. These targets tend to be co-expressed, and co-targeting these molecules is synergistic. NVP-BEZ235 is active in RCC cells in vitro; suggesting that concurrent PI3K and mTOR targeting in RCC warrants further investigation.
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影响因子：
6.2
作者：
Abou Youssif, Tamer;Fahmy, Mona Alam;Sircar, Kanishka
通讯作者：
Sircar, Kanishka
影响因子：
6.2
作者：
Hutson, Thomas E.;Figlin, Robert A.
通讯作者：
Figlin, Robert A.
影响因子：
11.5
作者：
Edling, Charlotte E.;Selvaggi, Federico;Falasca, Marco
通讯作者：
Falasca, Marco
影响因子：
45.3
作者：
McDermott, DF;Regan, MM;Atkins, MB
通讯作者：
Atkins, MB
DOI：
10.1016/j.bbapap.2007.10.003
发表时间：
2008-01-01
影响因子：
3.2
作者：
Marone, Romina;Cmijanovic, Vladimir;Wymann, Matthias P.
通讯作者：
Wymann, Matthias P.