Oncogenic BRAF is required for tumor growth and maintenance in melanoma models
Oncogenic BRAF is required for tumor growth and maintenance in melanoma models
复制标题
DOI：
10.1158/0008-5472.can-05-2720
复制
发表时间：
2006-01-15
期刊：
影响因子：
11.2
通讯作者：
Seshagiri, S
中科院分区：
文献类型：
--
作者：
Hoeflich, MP;Gray, DC;Seshagiri, S
在肿瘤学中开发激酶抑制剂的通常范例是使用具有可接受的代谢特性的高亲和力概念验证抑制剂来进行关键靶标验证实验。这种方法需要大量的药物化学知识，并且可能会因药物毒性和测试分子的脱靶活性而混淆。作为更好的替代方案，我们开发了可诱导的短发夹 RNA 异种移植模型来检查抑制致癌 BRAF 的体内功效。我们的结果表明，在这些模型中，BRAF 抑制导致的肿瘤消退是可诱导的、可逆的且受到严格调控。对肿瘤消退的分析表明，BRAF 的主要作用机制是增加肿瘤细胞增殖和存活。在转移性黑色素瘤模型中，根据体内生物发光成像的结果，条件性 BRAF 抑制减缓了全身肿瘤的生长。综上所述，功能获得性 BRAF 信号传导与体内致瘤性密切相关，证实 BRAF 是小分子和 RNA 干扰疗法的重要靶点。
The usual paradigm for developing kinase inhibitors in oncology is to use a high-affinity proof-of-concept inhibitor with acceptable metabolic properties for key target validation experiments. This approach requires substantial medicinal chemistry and can be confounded by drug toxicity and off target activities of the test molecule. As a better alternative, we have developed inducible short-hairpin RNA xenograft models to examine the in vivo efficacy of inhibiting oncogenic BRAF. Our results show that tumor regression resulting from BRAF suppression is inducible, reversible, and tightly regulated in these models. Analysis of regressing tumors showed the primary mechanism of action for BRAF to be increased tumor cell proliferation and survival. In a metastatic melanoma model, conditional BRAF suppression slowed systemic tumor growth as determined by in vivo bioluminescence imaging. Taken together, gain-of-function BRAF signaling is strongly associated with in vivo tumorigenicity, confirming BRAF as an important target for small-molecule and RNA interference-based therapeutics.