How to Target Activated Ras Proteins: Direct Inhibition vs. Induced Mislocalization.
How to Target Activated Ras Proteins: Direct Inhibition vs. Induced Mislocalization.
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DOI：
10.2174/1389557515666151001154002
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Mattingly RR
中科院分区：
文献类型：
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作者：
Brock EJ;Ji K;Reiners JJ;Mattingly RR
致癌的RAS蛋白是一组重要的人类癌症的驱动力，而野生型、未突变的RAS蛋白可能导致更多的癌症的恶性表型。靶向激活的RAS蛋白的总体挑战在治疗癌症方面有很大的希望，但这个目标还没有实现。已经投入了大量的努力和资源来抑制RAS，但到目前为止，这些能量在临床上几乎没有什么影响。直接以激活的RAS蛋白为靶点的尝试面临许多障碍，包括由生化水平的功能丧失所产生的功能获得致癌活性的根本性质。然而，最近在临床前取得了非常有希望的进展。目前已应用于临床的主要策略是通过阻断RAS的翻译后修饰和诱导其错误定位来间接抑制激活的RAS。虽然这些通过抑制法尼基转移酶(FTase)间接靶向RAS的努力是合理设计的，但这种策略没有充分注意RAS亚型之间的区别。这导致了随后针对K-RAS驱动的肺癌、结肠癌和胰腺癌的大规模临床试验的失败。尽管有这些挫折，通过诱导RAS的错误定位来间接靶向激活的RAS的努力仍然存在。FTase抑制剂可能仍有一定的临床应用价值，可能与他汀类药物或其他药物联合使用。通过中断RAS的棕榈酰化循环或与伴侣蛋白的相互作用来诱导RAS错误定位的替代方法还处于开发的早期阶段。
Oncogenic Ras proteins are a driving force in a significant set of human cancers and wild-type, unmutated Ras proteins likely contribute to the malignant phenotype of many more. The overall challenge of targeting activated Ras proteins has great promise to treat cancer, but this goal has yet to be achieved. Significant efforts and resources have been committed to inhibiting Ras, but these energies have so far made little impact in the clinic. Direct attempts to target activated Ras proteins have faced many obstacles, including the fundamental nature of the gain-of-function oncogenic activity being produced by a loss-of-function at the biochemical level. Nevertheless, there has been very promising recent pre-clinical progress. The major strategy that has so far reached the clinic aimed to inhibit activated Ras indirectly through blocking its post-translational modification and inducing its mislocalization. While these efforts to indirectly target Ras through inhibition of farnesyl transferase (FTase) were rationally designed, this strategy suffered from insufficient attention to the distinctions between the isoforms of Ras. This led to subsequent failures in large-scale clinical trials targeting K-Ras driven lung, colon, and pancreatic cancers. Despite these setbacks, efforts to indirectly target activated Ras through inducing its mislocalization have persisted. It is plausible that FTase inhibitors may still have some utility in the clinic, perhaps in combination with statins or other agents. Alternative approaches for inducing mislocalization of Ras through disruption of its palmitoylation cycle or interaction with chaperone proteins are in early stages of development.