Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery?
Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery?
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DOI：
10.1158/1078-0432.ccr-14-3214
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发表时间：
2015-04-15
期刊：
影响因子：
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通讯作者：
Philips MR
中科院分区：
文献类型：
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作者：
Cox AD;Der CJ;Philips MR
RAS蛋白的生物活性需要膜结合，这使得这种结合成为抗RAS治疗的逻辑靶点。通过法尼基类异戊二烯对RAS蛋白进行脂质修饰是该关联的必要步骤，并且是一个酶促过程。因此，法尼基转移酶抑制剂（FTIs）被开发为潜在的抗ras药物。fti作为抗癌药物缺乏疗效被广泛认为表明阻断RAS膜关联是一种有缺陷的癌症治疗方法。然而，对RAS修饰和贩运的深入了解表明，这是一个错误的结论。在fti存在的情况下，KRAS和NRAS（癌症中最常发生突变的RAS亚型）成为替代修饰的底物，仍然可以与膜结合，并且仍然可以发挥作用。因此，FTIs的失败并不是因为阻断RAS膜结合是一种无效的方法，而是因为FTIs未能完成这一任务。最近关于RAS异构体运输和RAS亚细胞定位调控的发现重新激起了人们对这些过程的兴趣。特别是，对调节RAS与质膜、内膜和细胞质溶胶相互作用的棕榈酰化/去棕榈酰化循环以及RAS伴侣的潜在重要性的理解的提高，导致了新的方法。验证和靶向其他酶调节的翻译后修饰的努力也在进行中。在这篇综述中，我们回顾了经验教训，描述了当前的艺术状态，并强调了具有挑战性但有希望的方向，以实现破坏RAS膜结合和亚细胞定位的目标，以开发抗RAS药物。
RAS proteins require membrane association for their biological activity, making this association a logical target for anti-RAS therapeutics. Lipid modification of RAS proteins by a farnesyl isoprenoid is an obligate step in that association, and is an enzymatic process. Accordingly, farnesyltransferase inhibitors (FTIs) were developed as potential anti-RAS drugs. The lack of efficacy of FTIs as anti-cancer drugs was widely seen as indicating that blocking RAS membrane association was a flawed approach to cancer treatment. However, a deeper understanding of RAS modification and trafficking has revealed that this was an erroneous conclusion. In the presence of FTIs, KRAS and NRAS, which are the RAS isoforms most frequently mutated in cancer, become substrates for alternative modification, can still associate with membranes, and can still function. Thus, FTIs failed not because blocking RAS membrane association is an ineffective approach, but because FTIs failed to accomplish that task. Recent findings regarding RAS isoform trafficking and the regulation of RAS subcellular localization have rekindled interest in efforts to target these processes. In particular, improved understanding of the palmitoylation/depalmitoylation cycle that regulates RAS interaction with the plasma membrane, endomembranes and cytosol, and of the potential importance of RAS chaperones, have led to new approaches. Efforts to validate and target other enzymatically regulated post-translational modifications are also ongoing. In this review, we revisit lessons learned, describe the current state of the art, and highlight challenging but promising directions to achieve the goal of disrupting RAS membrane association and subcellular localization for anti-RAS drug development.