Overcoming acute, adaptive BRAF inhibitor resistance in melanoma

描述（申请人提供）：2010年被癌症科学家和医生称为“黑色素瘤年”。2011年，我们见证了FDA批准BRAF抑制剂（vemurafenib/Zelboraf）用于治疗晚期黑色素瘤。尽管BRAF抑制剂可以诱导超过50%的前所未有的应答率，但早期实现的大多数肿瘤应答是部分的（即，急性、适应性抵抗），并且大多数最初应答的患者后来遭受疾病进展（即，获得性耐药性）。事实上，由BRAF抑制剂诱导的部分消退的黑色素瘤经常由于获得性耐药性而在以后让位于肿瘤再生长。因此，克服BRAF抑制剂耐药性有望显著提高黑色素瘤患者的存活率。我们建议通过了解早期（适应性，非遗传性）和晚期（遗传性）耐药机制来实现这一重要目标，以便有效地设计基于共同分母核心途径的组合靶向治疗。基于目前正在进行同行评审的数据，我们假设早期和晚期耐药是机械联系的，表观遗传重编程在早期适应性耐药中起主导作用。Lo实验室在整合“组学”和功能分析以揭示BRAF治疗患者的获得性耐药机制方面有着良好的记录。这些研究已经激发了组合治疗策略（例如BRAF + MEK抑制剂），并取得了令人鼓舞的早期结果。我们在目标1中建议利用全外显子组测序来全面了解黑色素瘤中获得性（晚期）BRAF抑制剂耐药性的机制，以便为适应性（早期）耐药性的研究提供信息。在这里，理解遗传改变如何在特定细胞环境中赋予获得性耐药性将触发对这种细胞环境和急性适应性耐药性中隐含的候选途径的机制研究。在目标2中，我们提出了实验来研究特定的，相互关联的表观遗传途径，有助于一种形式的染色质介导的急性适应性耐药性。这一目标利用转录组测序并研究早期的适应性抗性作为一系列易于处理的表型状态。总的来说，我们高度转化的方法建立在创新的合作基础上，这些合作在产生新的临床概念方面已经证明是富有成效的。将黑色素瘤如何抵抗BRAF抑制剂的知识转化回临床，有望使2010年黑色素瘤的转折点成为一个时代的故事。

DESCRIPTION (provided by applicant): 2010 has been called the "Year of Melanoma" by cancer scientists and physicians. In 2011, we witnessed the FDA approval of a BRAF inhibitor (vemurafenib/Zelboraf) for the treatment of advanced melanoma. Although BRAF inhibitors can induce unprecedented response rates in excess of 50%, most tumor responses achieved early are partial (i.e., acute, adaptive resistance), and most patients who initially respond later suffe from disease progression (i.e., acquired drug resistance). In fact, partially regressed melanomas induced by BRAF inhibitors frequently give way to tumor regrowth later due to acquired drug resistance. Thus, overcoming BRAF inhibitor resistance promises to significantly advance melanoma patient survivability. We propose achieving this important goal by understanding both early (adaptive, non-genetic) and late (genetic) mechanisms of drug resistance in order to effectively devise combinatorial targeted therapies based on common denominator core pathways. Based on data now under peer review, we hypothesize that early and late drug resistance are mechanistically linked and that epigenetic reprogramming plays a dominant role in early, adaptive drug resistance. The Lo Laboratory has a proven track record in integrating "omic" and functional analyses to uncover acquired resistance mechanisms operative in BRAF inhibitor-treated patients. These studies have already inspired combinatorial treatment strategies (e.g. BRAF + MEK inhibitors) with encouraging early results. We propose in Aim 1 to leverage whole-exome sequencing to comprehensively understand the mechanisms of acquired (late) BRAF inhibitor resistance in melanoma in order to inform the study of adaptive (early) drug resistance. Here, understanding how a genetic alteration confers acquired drug resistance in a specific cell context will trigger mechanistic studies into this cell context and the implicatd candidate pathway in acute, adaptive resistance. In Aim 2, we propose experiments to study specific, inter-related epigenetic pathways that contribute to a form of chromatin-mediated acute, adaptive drug resistance. This aim leverages transcriptomic sequencing and studies early, adaptive resistance as a series of tractable phenotypic states. Overall, our highly translational approaches are founded in innovative collaborations that have already proven productive in yielding novel clinical concepts. Translating knowledge of how melanomas resist BRAF inhibitors back to the clinic promises to make the 2010 melanoma turning point a story for the ages.