In vivo MAPK reporting reveals the heterogeneity in tumoral selection of resistance to RAF inhibitors.
In vivo MAPK reporting reveals the heterogeneity in tumoral selection of resistance to RAF inhibitors.
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DOI：
10.1158/0008-5472.can-13-1628
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发表时间：
2013-12-01
期刊：
影响因子：
11.2
通讯作者：
Aplin AE
中科院分区：
文献类型：
--
作者：
Basile KJ;Abel EV;Dadpey N;Hartsough EJ;Fortina P;Aplin AE
在突变型braf驱动的黑色素瘤中，ERK1/2丝裂原活化蛋白激酶（MAPKs）的激活赋予了对RAF抑制剂vemurafenib和dabrafenib的抗性。了解耐药性如何发展的方法对于优化患者中RAF抑制剂的临床应用非常重要。在这里，我们报告了一种新的ERK1/2报告系统的发展，该系统提供了一种非侵入性的、定量的、时间的体内RAF抑制剂疗效分析。该系统的使用揭示了与获得性RAF抑制抗性相关的ERK1/2再激活水平的异质性。我们在treatment-naïve细胞群中发现了几种不同的新型和已知的耐药肿瘤分子变化，包括BRAF V600E变异和HRAS突变，这两种变化都是ERK1/2再激活和耐药所必需和充分的。我们的工作在理解RAF抑制剂耐药性和耐药性机制的异质性方面取得了进展，这些机制来自恶性细胞群。
Activation of the ERK1/2 mitogen-activated protein kinases (MAPKs) confers resistance to the RAF inhibitors vemurafenib and dabrafenib in mutant BRAF-driven melanomas. Methods to understand how resistance develops are important to optimize the clinical utility of RAF inhibitors in patients. Here we report the development of a novel ERK1/2 reporter system that provides a non-invasive, quantitative and temporal analysis of RAF inhibitor efficacy in vivo. Use of this system revealed heterogeneity in the level of ERK1/2 reactivation associated with acquired resistance to RAF inhibition. We identified several distinct novel and known molecular changes in resistant tumors emerging from treatment-naïve cell populations including BRAF V600E variants and HRAS mutation, both of which were required and sufficient for ERK1/2 reactivation and drug resistance. Our work offers an advance in understanding RAF inhibitor resistance and the heterogeneity in resistance mechanisms, which emerge from a malignant cell population.