Selective and Potent Raf Inhibitors Paradoxically Stimulate Normal Cell Proliferation and Tumor Growth
Selective and Potent Raf Inhibitors Paradoxically Stimulate Normal Cell Proliferation and Tumor Growth
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DOI：
10.1158/1535-7163.mct-10-0181
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发表时间：
2010-08-01
影响因子：
5.7
通讯作者：
Burgess, Teresa L.
中科院分区：
文献类型：
--
作者：
Carnahan, Josette;Beltran, Pedro J.;Burgess, Teresa L.
Raf抑制剂正在进行临床研究，特别是在B-Raf中携带频繁激活突变的肿瘤类型患者中。在这里，我们表明，细胞系和肿瘤窝藏突变B-Raf敏感的一系列新的Raf抑制剂（如。例如，在一个实施例中，（V600 E）B-Raf A375，对细胞的IC（50）= 2 nmol/L;对肿瘤异种移植物的艾德（50）= 1.3 mg/kg）。然而，在具有野生型B-Raf的细胞和肿瘤中，暴露于Raf抑制剂导致有丝分裂原活化蛋白激酶信号传导的剂量依赖性和持续活化。在这些细胞系中的一些中，Raf抑制导致进入细胞周期，增强增殖，并显著刺激体内肿瘤生长。抑制与结构不同的Raf抑制剂或异构体特异性小干扰RNA敲低Raf表明，这些影响直接通过Raf介导。无论是A-Raf还是C-Raf，都以一种特定的方式介导Raf受体诱导的丝裂原活化蛋白激酶途径的激活。在体外和体内的恶性和正常细胞中观察到Raf抑制的这些矛盾效应。食管和胃中正常上皮细胞的增生在测试了所有有效Raf抑制剂的小鼠（n = 8）中是明显的。这些结果暗示Raf抑制剂可能在患者中诱导意想不到的正常细胞和肿瘤组织增殖。Mol Cancer Ther; 9（8）; 2399-410. (C)2010年AACR。
Raf inhibitors are under clinical investigation, specifically in patients with tumor types harboring frequent activating mutations in B-Raf. Here, we show that cell lines and tumors harboring mutant B-Raf were sensitive to a novel series of Raf inhibitors (e. g., (V600E)B-Raf A375, IC(50) on cells = 2 nmol/L; ED(50) on tumor xenografts = 1.3 mg/kg). However, in cells and tumors with wild-type B-Raf, exposure to Raf inhibitors resulted in a dose-dependent and sustained activation of mitogen-activated protein kinase signaling. In some of these cell lines, Raf inhibition led to entry into the cell cycle, enhanced proliferation, and significantly stimulated tumor growth in vivo. Inhibition with structurally distinct Raf inhibitors or isoform-specific small interfering RNA knockdown of Raf showed that these effects were mediated directly through Raf. Either A-Raf or C-Raf mediated the Raf inhibitor-induced mitogen-activated protein kinase pathway activation in an inhibitor-specific manner. These paradoxical effects of Raf inhibition were seen in malignant and normal cells in vitro and in vivo. Hyperplasia of normal epithelial cells in the esophagus and the stomach was evident in mice with all efficacious Raf inhibitors (n = 8) tested. An implication of these results is that Raf inhibitors may induce unexpected normal cell and tumor tissue proliferation in patients. Mol Cancer Ther; 9(8); 2399-410. (C) 2010 AACR.