Targeting the RAS oncogene.
Targeting the RAS oncogene.
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靶向RAS癌基因。
DOI：
10.1517/14728222.2013.764990
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发表时间：
2013-05
影响因子：
5.8
通讯作者：
Faller DV
中科院分区：
文献类型：
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作者：
Takashima A;Faller DV
Ras蛋白（K-Ras、N-Ras、H-Ras）是GTPases，其功能是多种关键细胞活动的分子开关，其功能在正常细胞中受到严格且时间性的调节。RAS基因中的致癌突变产生组成型活性Ras蛋白，可导致肿瘤细胞不受控制的增殖或存活。本文讨论了三种针对癌症中Ras通路的治疗方法：1）Ras本身，2）Ras下游通路，3）合成致死性。最常用的方法是靶向Ras下游信号传导，特别是PI 3 K-AKT-mTOR和Raf-MEK途径，因为它们通常是具有高Ras信号传导的癌症中的主要致癌驱动因素。虽然Ras的直接靶向在临床上尚未成功，但在临床前研究中正在研究的新方法，如基于RNA干扰的方法和合成致死方法，有望在临床应用中获得巨大潜力。当前和新兴疗法的挑战包括缺乏“肿瘤特异性”以及它们对“依赖”异常Ras信号传导存活的那些癌症的限制。虽然新方法有可能克服这些局限性，但它们也强调了稳健的临床前研究和双向转化研究对于Ras相关靶向疗法成功临床开发的重要性。
The Ras proteins (K-Ras, N-Ras, H-Ras) are GTPases that function as molecular switches for a variety of critical cellular activities and their function is tightly and temporally regulated in normal cells. Oncogenic mutations in the RAS genes, which create constitutively-active Ras proteins, can result in uncontrolled proliferation or survival in tumor cells. The paper discusses three therapeutic approaches targeting the Ras pathway in cancer: 1) Ras itself, 2) Ras downstream pathways, and 3) synthetic lethality. The most adopted approach is targeting Ras downstream signaling, and specifically the PI3K-AKT-mTOR and Raf-MEK pathways, as they are frequently major oncogenic drivers in cancers with high Ras signaling. Although direct targeting of Ras has not been successful clinically, newer approaches being investigated in preclinical studies, such as RNA interference-based and synthetic lethal approaches, promise great potential for clinical application. The challenges of current and emerging therapeutics include the lack of “tumor specificity” and their limitation to those cancers which are “dependent” upon aberrant Ras signaling for survival. While the newer approaches have the potential to overcome these limitations, they also highlight the importance of robust preclinical studies and bidirectional translational research for successful clinical development of Ras-related targeted therapies.
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影响因子：
45.3
作者：
Abou-Alfa, Ghassan K.;Schwartz, Lawrence;Saltz, Leonard B.
通讯作者：
Saltz, Leonard B.
影响因子：
45.3
作者：
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通讯作者：
Vokes, EE
影响因子：
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作者：
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通讯作者：
Clarke, PA
影响因子：
45.3
作者：
Alberts, SR;Schroeder, M;Fitch, TR
通讯作者：
Fitch, TR
影响因子：
3
作者：
通讯作者：
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