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Targeting the RAS oncogene

机译：靶向RAS癌基因

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Introduction: The Ras proteins (K-Ras, N-Ras, and 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. Areas covered: The paper discusses three therapeutic approaches targeting the Ras pathway in cancer: i) Ras itself, ii) Ras downstream pathways, and iii) 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. Expert opinion: The challenges of current and emerging therapeutics include the lack of "tumor specificity" and their limitation to those cancers which are "dependent" on 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.
机译：简介：Ras蛋白（K-Ras，N-Ras和H-Ras）是GTPases，可作为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和暂时的调节。 RAS基因中的致癌突变会产生组成性活性Ras蛋白，从而导致肿瘤细胞的增殖或存活不受控制。涵盖的领域：本文讨论了针对癌症中Ras途径的三种治疗方法：i）Ras自身，ii）Ras下游途径，iii）合成杀伤力。最常用的方法是针对Ras下游信号传导，尤其是PI3K-AKT-mTOR和Raf-MEK途径，因为它们通常是具有高Ras信号传导的癌症的主要致癌驱动因素。尽管直接靶向Ras在临床上还没有成功，但临床前研究中正在研究的新方法，例如基于RNA干扰的方法和合成致死方法，都有望在临床上应用。专家意见：当前和新兴疗法的挑战包括缺乏“肿瘤特异性”及其对那些“依赖”异常Ras信号存活的癌症的局限性。尽管较新的方法有可能克服这些局限性，但它们也强调了可靠的临床前研究和双向转化研究对与Ras相关的靶向疗法的成功临床开发的重要性。

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