New Mechanisms of Resistance to MEK Inhibitors in Melanoma Revealed by Intravital Imaging.
New Mechanisms of Resistance to MEK Inhibitors in Melanoma Revealed by Intravital Imaging.
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DOI：
10.1158/0008-5472.can-17-1653
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发表时间：
2018-01-15
期刊：
影响因子：
11.2
通讯作者：
Bear JE
中科院分区：
文献类型：
--
作者：
Brighton HE;Angus SP;Bo T;Roques J;Tagliatela AC;Darr DB;Karagoz K;Sciaky N;Gatza ML;Sharpless NE;Johnson GL;Bear JE
最初在癌症患者中有效的靶向治疗几乎总是在某个阶段产生耐药性，这是在癌症环境中使用任何分子靶向药物的固有挑战。在这项研究中，我们评估了转移性黑色素瘤对MAPK通路激酶抑制剂的耐药机制，作为确定限制耐药风险的候选策略的策略。为了研究纵向反应，我们开发了一种活体连续成像方法，该方法可以直接可视化诱导型RAF驱动的、包含荧光报告等位基因（tdTomatoLSL）的原发性黑色素瘤小鼠模型中的药物反应。使用该系统，我们从单细胞水平纵向观察了肿瘤的原位形成和进展。用选择性MEK 1/2抑制剂（MEKi）曲美替尼治疗的原发性小鼠肿瘤状态的可靠报告说明了初始药物应答和持续性的时间过程，随后出现耐药性。我们发现，邻近成束胶原蛋白的肿瘤细胞对MEKi的反应具有优先的持久性。来自所选处理时间点的无偏转录和激酶组重编程分析表明，耐药肿瘤中c-Kit和PI 3 K/AKT途径活化增加，沿着上皮基因表达增强和EMT下调特征，伴随MEKi耐药的发展。在使用与标准护理组合疗法一致的BRAF和MEK抑制剂同时治疗后观察到类似趋势，表明这些重编程事件并非仅特异于MEKi。总的来说，我们的研究结果阐明了黑色素瘤进展中肿瘤间质动力学与组织可塑性的整合，并为药物反应，持久性和耐药性的基础提供了新的见解。
Targeted therapeutics that are initially effective in cancer patients nearly invariably engender resistance at some stage, an inherent challenge in the use of any molecular targeted drug in cancer settings. In this study, we evaluated resistance mechanisms arising in metastatic melanoma to MAPK pathway kinase inhibitors, as a strategy to identify candidate strategies to limit risks of resistance. To investigate longitudinal responses, we developed an intravital serial imaging approach that can directly visualize drug response in an inducible RAF-driven, autochthonous murine model of melanoma incorporating a fluorescent reporter allele (tdTomatoLSL). Using this system, we visualized formation and progression of tumors in situ starting from the single cell level longitudinally over time. Reliable reporting of the status of primary murine tumors treated with the selective MEK1/2 inhibitor (MEKi) trametinib illustrated a time-course of initial drug response and persistence followed by the development of drug resistance. We found that tumor cells adjacent to bundled collagen had a preferential persistence in response to MEKi. Unbiased transcriptional and kinome reprogramming analyses from selected treatment time points suggested increased c-Kit and PI3K/AKT pathway activation in resistant tumors, along with enhanced expression of epithelial genes and EMT downregulation signatures with development of MEKi resistance. Similar trends were observed following simultaneous treatment with BRAF and MEK inhibitors aligned to standard of care combination therapy, suggesting these re-programming events were not specific to MEKi alone. Overall, our results illuminate the integration of tumor-stroma dynamics with tissue plasticity in melanoma progression and provide new insights into the basis for drug response, persistence and resistance.