Women's Cancers Section, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.
PLoS One. 2011;6(10):e25625. doi: 10.1371/journal.pone.0025625. Epub 2011 Oct 5.
Pazopanib is an FDA approved Vascular Endothelial Growth Factor Receptor inhibitor. We previously reported that it also inhibits tumor cell B-Raf activity in an experimental brain metastatic setting. Here, we determine the effects of different B-Raf genotypes on pazopanib efficacy, in terms of primary tumor growth and anti-angiogenesis. A panel of seven human breast cancer and melanoma cell lines harboring different mutations in the Ras-Raf pathway was implanted orthotopically in mice, and tumor growth, ERK1/2, MEK1/2 and AKT activation, and blood vessel density and permeability were analyzed. Pazopanib was significantly inhibitory to xenografts expressing either exon 11 mutations of B-Raf, or HER2 activated wild type B-Raf; no significant inhibition of a xenograft expressing the common V600E B-Raf mutation was observed. Decreased pMEK staining in the responsive tumors confirmed that B-Raf was targeted by pazopanib. Interestingly, pazopanib inhibition of tumor cell B-Raf also correlated with its anti-angiogenic activity, as quantified by vessel density and area. In conclusion, using pazopanib, tumor B-Raf status was identified as a significant determinant of both tumor growth and angiogenesis.
帕唑帕尼是一种经美国食品药品监督管理局批准的血管内皮生长因子受体抑制剂。我们之前曾报道过，在实验性脑转移模型中，它还能抑制肿瘤细胞 B-Raf 的活性。在此，我们根据原发肿瘤生长和抗血管生成的情况，确定不同 B-Raf 基因型对帕唑帕尼疗效的影响。将一组携带 Ras-Raf 通路不同突变的七种人乳腺癌和黑色素瘤细胞系原位植入小鼠体内，分析肿瘤生长、ERK1/2、MEK1/2 和 AKT 的激活以及血管密度和通透性。帕唑帕尼对表达 B-Raf 外显子 11 突变或 HER2 激活野生型 B-Raf 的异种移植物具有显著抑制作用；对表达常见 V600E B-Raf 突变的异种移植物则没有明显抑制作用。在有反应的肿瘤中，pMEK 染色减少证实了帕唑帕尼靶向了 B-Raf。有趣的是，帕唑帕尼对肿瘤细胞 B-Raf 的抑制作用也与其抗血管生成活性相关，可通过血管密度和面积进行量化。总之，使用帕唑帕尼可确定肿瘤 B-Raf 状态是肿瘤生长和血管生成的重要决定因素。
