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
Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94143-0875, USA.
Nature. 2008 Oct 2;455(7213):679-83. doi: 10.1038/nature07260. Epub 2008 Aug 17.
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.
Myc是一种多效性的碱性螺旋-环-螺旋亮氨酸拉链转录因子，它协调多种细胞内和细胞外程序的表达，这些程序共同对体细胞的生长和增殖至关重要。原则上，这使得抑制Myc成为治疗多种癌症的一种有吸引力的药理学方法。然而，由于缺乏直接证据表明抑制Myc具有治疗效果，担心其会通过抑制正常组织的增殖而引发严重副作用，以及设计Myc抑制药物存在实际困难，人们的热情有所降低。我们通过可逆的、全身性表达显性干扰Myc突变体，在Ras诱导的肺腺癌临床前小鼠模型中对全身性抑制Myc的治疗效果和副作用进行了基因建模。我们发现，抑制Myc会引发初期和已形成的肺肿瘤迅速消退，这确定了内源性Myc功能在体内维持Ras依赖性肿瘤中的意外作用。全身性抑制Myc对正常再生组织也有深远影响。然而，这些影响在较长时间内耐受性良好，且迅速且完全可逆。我们的数据证明了靶向Myc（许多致癌信号的常见下游途径）作为一种有效、高效且肿瘤特异性癌症治疗方法的可行性。
