Discovery Oncology, Hoffmann-La Roche, Inc., Nutley, New Jersey, USA.
Cancer Res. 2010 Jul 1;70(13):5518-27. doi: 10.1158/0008-5472.CAN-10-0646. Epub 2010 Jun 15.
The BRAF(V600E) mutation is common in several human cancers, especially melanoma. RG7204 (PLX4032) is a small-molecule inhibitor of BRAF(V600E) kinase activity that is in phase II and phase III clinical testing. Here, we report a preclinical characterization of the antitumor activity of RG7204 using established in vitro and in vivo models of malignant melanoma. RG7204 potently inhibited proliferation and mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase and ERK phosphorylation in a panel of tumor cell lines, including melanoma cell lines expressing BRAF(V600E) or other mutant BRAF proteins altered at codon 600. In contrast, RG7204 lacked activity in cell lines that express wild-type BRAF or non-V600 mutations. In several tumor xenograft models of BRAF(V600E)-expressing melanoma, we found that RG7204 treatment caused partial or complete tumor regressions and improved animal survival, in a dose-dependent manner. There was no toxicity observed in any dose group in any of the in vivo models tested. Our findings offer evidence of the potent antitumor activity of RG7204 against melanomas harboring the mutant BRAF(V600E) gene.
BRAF(V600E) 突变常见于多种人类癌症，尤其是黑色素瘤。RG7204（PLX4032）是一种小分子 BRAF(V600E) 激酶活性抑制剂，目前正在进行 II 期和 III 期临床试验。在此，我们报告了 RG7204 对恶性黑色素瘤的体外和体内模型的抗肿瘤活性的临床前特征。RG7204 能有效抑制一组肿瘤细胞系的增殖和丝裂原激活蛋白/细胞外信号调节激酶（ERK）激酶和 ERK 磷酸化，包括表达 BRAF(V600E) 或其他在 600 密码子处改变的突变 BRAF 蛋白的黑色素瘤细胞系。相比之下，RG7204 在表达野生型 BRAF 或非 V600 突变的细胞系中没有活性。在几种表达 BRAF(V600E)的黑色素瘤的肿瘤异种移植模型中，我们发现 RG7204 治疗以剂量依赖性方式导致部分或完全肿瘤消退，并改善了动物的存活率。在所有测试的体内模型中，任何剂量组均未观察到毒性。我们的研究结果为 RG7204 针对携带突变 BRAF(V600E)基因的黑色素瘤提供了强有力的抗肿瘤活性证据。
