Epizyme, Inc., 400 Technology Square, Cambridge, MA 02139, USA.
Epizyme, Inc., 400 Technology Square, Cambridge, MA 02139, USA.
Cell Chem Biol. 2017 Sep 21;24(9):1120-1147. doi: 10.1016/j.chembiol.2017.08.020.
Comprehensive whole-exome sequencing, DNA copy-number determination, and transcriptomic analyses of diverse cancers have greatly expanded our understanding of the biology of many tumor types. In addition to mutations in the common cell-of-origin specific driver mutations, these studies have also revealed a large number of loss-of-function and gain-of-function mutations in chromatin-modifying proteins (CMPs). This has revealed that epigenetic dysregulation is a common feature of most pediatric and adult cancers. Many specific and potent inhibitors have been developed for multiple CMP classes, which have assisted in elucidating the role of epigenetics as well as epigenetic vulnerabilities in these cancer types. Clinical trials with numerous CMP inhibitors are also currently in progress to evaluate the therapeutic potential of epigenetic inhibitors. In this review, we aim to provide a summary of genetic mutations in epigenetic genes and a review of CMP inhibitors suitable for preclinical studies or currently in clinical trials. Additionally, we highlight the CMPs for which potent inhibitors have not been developed and additional research focus should be dedicated.
全面的全外显子组测序、DNA 拷贝数测定和转录组分析极大地扩展了我们对许多肿瘤类型生物学的理解。除了常见的起源细胞特异性驱动突变外，这些研究还揭示了大量染色质修饰蛋白（CMP）的功能丧失和功能获得突变。这表明表观遗传失调是大多数儿科和成人癌症的共同特征。已经为多个 CMP 类开发了许多特异性和有效的抑制剂，这有助于阐明这些癌症类型中表观遗传学的作用及其脆弱性。目前也正在进行许多 CMP 抑制剂的临床试验，以评估表观遗传抑制剂的治疗潜力。在这篇综述中，我们旨在提供表观遗传基因中遗传突变的概述，并回顾适合临床前研究或目前正在临床试验中的 CMP 抑制剂。此外，我们还强调了尚未开发出有效抑制剂的 CMP，并应专注于进一步研究。
