Modelling Myc inhibition as a cancer therapy.
Modelling Myc inhibition as a cancer therapy.
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DOI：
10.1038/nature07260
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发表时间：
2008-10-02
期刊：
影响因子：
64.8
通讯作者：
Evan, Gerard I.
中科院分区：
文献类型：
--
作者：
Soucek, Laura;Whitfield, Jonathan;Martins, Carla P.;Finch, Andrew J.;Murphy, Daniel J.;Sodir, Nicole M.;Karnezis, Anthony N.;Swigart, Lamorna Brown;Nasi, Sergio;Evan, Gerard I.
Myc是一种多效性碱性螺旋-环-螺旋亮氨酸拉链转录因子，其协调多种细胞内和细胞外程序的表达，这些程序一起对于体细胞的生长和扩增是必需的。原则上，这使得抑制Myc成为治疗不同类型癌症的有吸引力的药理学方法。然而，由于缺乏直接证据表明Myc抑制在治疗上有效，担心它会通过抑制正常组织的增殖而引起严重的副作用，以及设计Myc抑制药物的实际困难，热情已经减弱。我们在Ras诱导的肺腺癌的临床前小鼠模型中，通过显性干扰Myc突变体的可逆、系统表达，对全身Myc抑制的治疗影响和副作用进行了遗传建模。我们表明，Myc抑制触发早期和建立肺肿瘤的快速消退，定义了一个意想不到的作用，内源性Myc功能在维持Ras依赖性肿瘤在体内。全身性Myc抑制也对正常再生组织产生深远影响。然而，这些作用在较长时间内耐受良好，并且迅速和完全可逆。我们的数据证明了靶向Myc的可行性，Myc是许多致癌信号的常见下游通道，是一种有效，高效和肿瘤特异性的癌症治疗方法。
Myc is a pleiotropic basic helix–loop–helix leucine zipper transcription factor that coordinates expression of the diverse intracellular and extracellular programs that together are necessary for growth and expansion of somatic cells. In principle, this makes inhibition of Myc an attractive pharmacological approach for treating diverse types of cancer. However, enthusiasm has been muted by lack of direct evidence that Myc inhibition would be therapeutically efficacious, concerns that it would induce serious side effects by inhibiting proliferation of normal tissues, and practical difficulties in designing Myc inhibitory drugs. We have modelled genetically both the therapeutic impact and the side effects of systemic Myc inhibition in a preclinical mouse model of Ras-induced lung adenocarcinoma by reversible, systemic expression of a dominant-interfering Myc mutant. We show that Myc inhibition triggers rapid regression of incipient and established lung tumours, defining an unexpected role for endogenous Myc function in the maintenance of Ras-dependent tumours in vivo. Systemic Myc inhibition also exerts profound effects on normal regenerating tissues. However, these effects are well tolerated over extended periods and rapidly and completely reversible. Our data demonstrate the feasibility of targeting Myc, a common downstream conduit for many oncogenic signals, as an effective, efficient and tumour-specific cancer therapy.
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