Activated Ras as a Therapeutic Target: Constraints on Directly Targeting Ras Isoforms and Wild-Type versus Mutated Proteins.
Activated Ras as a Therapeutic Target: Constraints on Directly Targeting Ras Isoforms and Wild-Type versus Mutated Proteins.
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DOI：
10.1155/2013/536529
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发表时间：
2013
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影响因子：
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通讯作者：
Mattingly RR
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文献类型：
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作者：
Mattingly RR
选择性和直接靶向活化Ras的能力将为治疗由致癌Ras突变驱动的众多癌症提供巨大的效用。由过度激活的野生型Ras蛋白驱动的疾病患者，如1型神经纤维瘤病，也可能从这方面的进展中受益。活化的Ras是一个极具挑战性的直接药物靶点，因为破坏蛋白质的固有困难：蛋白质相互作用是其激活和功能的基础。通过间接路线对Ras进行了重大投资。抑制法尼基转移酶以阻止Ras成熟在大型临床试验中失败。这一令人失望的结果可能的原因包括Ras亚型的显著和未被重视的差异。抑制法尼基转移酶将被证明对由活化的H-Ras驱动的疾病有效，这仍然是合理的。目前进入临床试验的药物的主要焦点是抑制活化Ras的下游途径，例如，曲美替尼，一种一流的MEK抑制剂。激活Ras驱动的信号传导的复杂性表明，通过这种方法有效抑制致癌转导将是困难的，通过切换到平行通路可能会出现耐药性。持久的疾病反应可能需要几个下游靶点的组合阻断。
The ability to selectively and directly target activated Ras would provide immense utility for treatment of the numerous cancers that are driven by oncogenic Ras mutations. Patients with disorders driven by overactivated wild-type Ras proteins, such as type 1 neurofibromatosis, might also benefit from progress made in that context. Activated Ras is an extremely challenging direct drug target due to the inherent difficulties in disrupting the protein:protein interactions that underlie its activation and function. Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials. Likely reasons for this disappointing outcome include the significant and underappreciated differences in the isoforms of Ras. It is still plausible that inhibition of farnesyl transferase will prove effective for disease that is driven by activated H-Ras. The principal current focus of drugs entering clinic trial is inhibition of pathways downstream of activated Ras, for example, trametinib, a first-in-class MEK inhibitor. The complexity of signaling that is driven by activated Ras indicates that effective inhibition of oncogenic transduction through this approach will be difficult, with resistance being likely to emerge through switch to parallel pathways. Durable disease responses will probably require combinatorial block of several downstream targets.