BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis
BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis
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DOI：
10.1158/0008-5472.can-04-1443
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发表时间：
2004-10-01
期刊：
影响因子：
11.2
通讯作者：
Trail, PA
中科院分区：
文献类型：
--
作者：
Wilhelm, SM;Carter, C;Trail, PA
RAS/RAF信号通路是肿瘤细胞增殖和血管生成的重要介体。新型Bi-Aryl尿素湾43-9006是RAF-1的有效抑制剂，RAF-1是RAF/MEK/ERK信号通路的成员。其他表征表明，BAY 43-9006在体外抑制了野生型和V599E突变体Braf活性。此外，BAY 43-9006表现出与参与新血管形成和肿瘤进展的几种受体酪氨酸激酶的显着活性，包括血管内皮生长因子受体（VEGFR）-2，VEGFR-3，血小板衍生的生长因子受体beta，FIT-3，FIT-3，FIT-3，FIT-3，FIT-3，FIT-3，FIT-3，和C-Kit。在细胞机械测定中，BAY 43-9006显示出在结肠，胰腺和乳腺肿瘤细胞系中表达突变型KRAS或野生型或突变体BRAF的丝分裂原激活蛋白激酶途径的抑制表达突变的KRA对抑制有丝分裂原激活蛋白激酶途径的抑制不敏感43-9006。对于BAY 43-9006，还观察到对VEGFR-2，血小板衍生的生长因子受体P和VEGFR-3细胞受体自磷酸化的有效抑制作用。每天的口服剂量43-9006表现出在结肠，乳腺癌和非小细胞肺癌异种移植模型中的广谱抗肿瘤活性。免疫组织化学表明，抑制肿瘤生长的抑制与抑制细胞外信号调节激酶（ERKS）（ERKS）1/2磷酸化在所检查的三个异种移植模型中的两个中，与RAF/MEK/ERK途径的抑制相一致型号。使用抗丝氨酸CD31抗体在相同肿瘤切片中微血管密度和微血管区域的其他分析表明，在所有三种异种移植模型中，对新血管化的抑制作用显着抑制。这些数据表明，BAY 43-9006是一种新型的双重作用RAF激酶和VEGFR抑制剂，靶向肿瘤细胞增殖和肿瘤血管生成。
The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation and angiogenesis. The novel bi-aryl urea BAY 43-9006 is a potent inhibitor of Raf-1, a member of the RAF/MEK/ERK signaling pathway. Additional characterization showed that BAY 43-9006 suppresses both wild-type and V599E mutant BRAF activity in vitro. In addition, BAY 43-9006 demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular endothelial growth factor receptor (VEGFR)-2, VEGFR-3, platelet-derived growth factor receptor beta, Fit-3, and c-KIT. In cellular mechanistic assays, BAY 43-9006 demonstrated inhibition of the mitogen-activated protein kinase pathway in colon, pancreatic, and breast tumor cell lines expressing mutant KRAS or wild-type or mutant BRAF, whereas non-small-cell lung cancer cell lines expressing mutant KRAS were insensitive to inhibition of the mitogen-activated protein kinase pathway by BAY 43-9006. Potent inhibition of VEGFR-2, platelet-derived growth factor receptor P, and VEGFR-3 cellular receptor autophosphorylation was also observed for BAY 43-9006. Once daily oral dosing of BAY 43-9006 demonstrated broad-spectrum antitumor activity in colon, breast, and non-small-cell lung cancer xenograft models. Immunohistochemistry demonstrated a close association between inhibition of tumor growth and inhibition of the extracellular signal-regulated kinases (ERKs) 1/2 phosphorylation in two of three xenograft models examined, consistent with inhibition of the RAF/MEK/ERK pathway in some but not all models. Additional analyses of microvessel density and microvessel area in the same tumor sections using antimurine CD31 antibodies demonstrated significant inhibition of neovascularization in all three of the xenograft models. These data demonstrate that BAY 43-9006 is a novel dual action RAF kinase and VEGFR inhibitor that targets tumor cell proliferation and tumor angiogenesis.