Sorafenib, a Multikinase Inhibitor, Enhances the Response of Melanoma to Regional Chemotherapy
Sorafenib, a Multikinase Inhibitor, Enhances the Response of Melanoma to Regional Chemotherapy
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DOI：
10.1158/1535-7163.mct-10-0073
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发表时间：
2010-07-01
影响因子：
5.7
通讯作者：
Tyler, Douglas S.
中科院分区：
文献类型：
--
作者：
Augustine, Christina K.;Toshimitsu, Hiroaki;Tyler, Douglas S.
由于其固有的化疗耐药性，黑色素瘤对标准化疗反应不佳。多种遗传和分子缺陷，包括 BRaf 激酶基因的激活突变，与黑色素瘤有关，由此产生的调节增殖和凋亡的信号转导途径的改变被认为有助于其化疗耐药性。索拉非尼是一种针对 BRaf 激酶的多激酶抑制剂，已获得美国食品和药物管理局批准用于晚期肾细胞癌和肝细胞癌。尽管索拉非尼作为单一药物治疗黑色素瘤患者的前景不大，但最近的临床试验表明，与化疗联合使用时，它可能会带来更多益处。我们在一组 24 种人类黑色素瘤衍生细胞系和黑色素瘤动物模型中评估了索拉非尼增强美法仑（一种区域化疗剂）和替莫唑胺（用于黑色素瘤的全身和区域治疗）的细胞毒性作用的能力。在体外观察到不同细胞系对单独使用 10 μmol/L 索拉非尼的反应存在显着差异。对索拉非尼的反应与细胞外信号调节激酶 (ERK) 下调和 Mcl-1 表达丧失显着相关 (P < 0.05)。使用丝裂原激活蛋白激酶/ERK 激酶抑制剂 U0126 进行的实验表明，ERK 下调在观察到的效应中具有独特的作用。索拉非尼与马法兰或替莫唑胺联合使用可显着改善体外反应（P < 0.05）。在黑色素瘤动物模型中，索拉非尼联合局部美法仑或局部替莫唑胺比单独使用任一治疗方法更能有效减缓肿瘤生长。这些结果表明，索拉非尼联合化疗为在途黑色素瘤的局部治疗提供了一种增强化疗疗效的新方法。摩尔癌症治疗； 9(7)； 2090-101。 (C) 2010 AACR。
Melanoma responds poorly to standard chemotherapy due to its intrinsic chemoresistance. Multiple genetic and molecular defects, including an activating mutation in the BRaf kinase gene, are associated with melanoma, and the resulting alterations in signal transduction pathways regulating proliferation and apoptosis are thought to contribute to its chemoresistance. Sorafenib, a multikinase inhibitor that targets BRaf kinase, is Food and Drug Administration approved for use in advanced renal cell and hepatocellular carcinomas. Although sorafenib has shown little promise as a single agent in melanoma patients, recent clinical trials suggest that, when combined with chemotherapy, it may have more benefit. We evaluated the ability of sorafenib to augment the cytotoxic effects of melphalan, a regional chemotherapeutic agent, and temozolomide, used in systemic and regional treatment of melanoma, on a panel of 24 human melanoma-derived cell lines and in an animal model of melanoma. Marked differences in response to 10 mu mol/L sorafenib alone were observed in vitro across cell lines. Response to sorafenib significantly correlated with extracellular signal-regulated kinase (ERK) downregulation and loss of Mcl-1 expression (P < 0.05). Experiments with the mitogen-activated protein kinase/ERK kinase inhibitor U0126 suggest a unique role for ERK downregulation in the observed effects. Sorafenib in combination with melphalan or temozolomide led to significantly improved responses in vitro (P < 0.05). In the animal model of melanoma, sorafenib in combination with regional melphalan or regional temozolomide was more effective than either treatment alone in slowing tumor growth. These results show that sorafenib in combination with chemotherapy provides a novel approach to enhance chemotherapeutic efficacy in the regional treatment of in-transit melanoma. Mol Cancer Ther; 9(7); 2090-101. (C) 2010 AACR.