Parallel In Vivo Assessment of Drug Phenotypes at Various Time Points during Systemic BRAF Inhibition Reveals Tumor Adaptation and Altered Treatment Vulnerabilities.
Parallel In Vivo Assessment of Drug Phenotypes at Various Time Points during Systemic BRAF Inhibition Reveals Tumor Adaptation and Altered Treatment Vulnerabilities.
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DOI：
10.1158/1078-0432.ccr-15-2722
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发表时间：
2016-12-15
期刊：
影响因子：
--
通讯作者：
Langer R
中科院分区：
文献类型：
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作者：
Jonas O;Oudin MJ;Kosciuk T;Whitman M;Gertler FB;Cima MJ;Flaherty KT;Langer R
以BRAF抑制剂为基础的治疗对BRAF突变黑色素瘤的治疗有很高的应答率，但在绝大多数患者中持续时间有限。已发表的耐药机制研究表明，有许多肿瘤适应和信号转导旁路机制的例子，但没有深入了解预测哪种机制将占主导地位的生物标志物。在治疗期间同时监测同一肿瘤内多种适应机制的表型反应是难以捉摸的。这项研究报告了一种方法，以提供一个更全面的了解适应性肿瘤反应。在全身抑制BRAF的不同时间点，我们同时检测了12类被怀疑启用适应性逃逸机制的抑制剂的体内抗肿瘤活性。我们使用可植入的微型设备将多种化合物释放到肿瘤的不同区域，以独立地测量每种化合物的疗效，并在肿瘤进行全身BRAF治疗时重复这些测量。我们观察到在长期全身应用BRAF抑制剂之前、期间和之后对特定抑制剂的不同表型反应。我们的结果特别确定了PI3K、PDGFR、EGFR和HDAC抑制剂在全身BRAF抑制过程中变得明显更有效。对其他靶向抑制剂的敏感性基本保持不变，而对PLX4720的局部增量敏感性急剧下降。这些发现提示了几种耐药机制的冗余，并可能有助于确定更有效的联合治疗BRAF突变黑色素瘤的最佳成分。它们也代表了在治疗过程中动态测量同一肿瘤内自适应信号机制的新范式。
Treatment of BRAF-mutated melanoma tumors with BRAF inhibitor-based therapy produces high response rates, but of limited duration in the vast majority of patients. Published investigations of resistance mechanisms suggest numerous examples of tumor adaptation and signal transduction bypass mechanisms, but without insight into biomarkers that would predict which mechanism will predominate. Monitoring phenotypic response of multiple adaptive mechanisms simultaneously within the same tumor as it adapts during treatment has been elusive. This study reports on a method to provide a more complete understanding of adaptive tumor responses. We simultaneously measured in vivo anti-tumor activity of 12 classes of inhibitors which are suspected of enabling adaptive escape mechanisms, at various time points during systemic BRAF inhibition. We used implantable microdevices to release multiple compounds into distinct regions of a tumor to measure the efficacy of each compound independently, and repeated these measurements as tumors progressed on systemic BRAF treatment. We observed varying phenotypic responses to specific inhibitors before, during and after prolonged systemic treatment with BRAF inhibitors. Our results specifically identify PI3K, PDGFR, EGFR and HDAC inhibitors as becoming significantly more efficacious during systemic BRAF inhibition. The sensitivity to other targeted inhibitors remained mostly unchanged, while local incremental sensitivity to PLX4720 declined sharply. These findings suggest redundancy of several resistance mechanisms and may help identify optimal constituents of more effective combination therapy in BRAF-mutant melanoma. They also represent a new paradigm for dynamic measurement of adaptive signaling mechanisms within the same tumor during therapy.