Intrinsic cell-penetrating activity propels Omomyc from proof of concept to viable anti-MYC therapy
Intrinsic cell-penetrating activity propels Omomyc from proof of concept to viable anti-MYC therapy
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DOI：
10.1126/scitranslmed.aar5012
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发表时间：
2019-03-20
影响因子：
17.1
通讯作者：
Soucek, Laura
中科院分区：
文献类型：
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作者：
Beaulieu, Marie-Eve;Jauset, Toni;Soucek, Laura
长期以来，抑制MYC一直被认为是不可行的，尽管它在人类癌症中的关键作用使其成为治疗干预的理想靶点。人们认为它无法下药的一个原因是担心对正常组织产生灾难性的副作用。然而，我们之前设计了一种名为Oomyc的显性-负性MYC形式，并使用其条件转基因表达在体外和体内抑制MYC功能。Oomyc对MYC的抑制在各种癌症小鼠模型中产生了强大的治疗影响，仅引起轻微的、耐受性良好的和可逆的副作用。然而，到目前为止，Oomyc只被认为是原则的证明。与这一先入为主的概念相反，在这里，我们证明了纯化的Oomyc微型蛋白本身自发地渗透到癌细胞中，并有效地干扰了其中的MYC转录活性。在具有不同致癌基因突变谱的各种非小细胞肺癌实验模型中，Oomyc迷你蛋白的疗效证实了其在直接组织给药和全身给药后的治疗潜力，提供了Oomyc迷你蛋白是一种值得临床开发的有效MYC抑制剂的证据。
Inhibiting MYC has long been considered unfeasible, although its key role in human cancers makes it a desirable target for therapeutic intervention. One reason for its perceived undruggability was the fear of catastrophic side effects in normal tissues. However, we previously designed a dominant-negative form of MYC called Omomyc and used its conditional transgenic expression to inhibit MYC function both in vitro and in vivo. MYC inhibition by Omomyc exerted a potent therapeutic impact in various mouse models of cancer, causing only mild, well-tolerated, and reversible side effects. Nevertheless, Omomyc has been so far considered only a proof of principle. In contrast with that preconceived notion, here, we show that the purified Omomyc mini-protein itself spontaneously penetrates into cancer cells and effectively interferes with MYC transcriptional activity therein. Efficacy of the Omomyc mini-protein in various experimental models of non-small cell lung cancer harboring different oncogenic mutation profiles establishes its therapeutic potential after both direct tissue delivery and systemic administration, providing evidence that the Omomyc mini-protein is an effective MYC inhibitor worthy of clinical development.