K-Ras prenylation as a potential anticancer target.
K-Ras prenylation as a potential anticancer target.
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K-RAS前化作为潜在的抗癌靶标。
DOI：
10.1007/s10555-020-09902-w
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Hegedűs B
中科院分区：
文献类型：
--
作者：
Baranyi M;Buday L;Hegedűs B
KRAS是最常见的癌基因突变之一，是许多靶向治疗的负面预测因子。因此，迫切需要开发针对突变KRAS的靶向策略。一种可能的策略是破坏K-RAS膜的定位，这是其正常功能所必需的。在这篇综述中，我们总结了关于K-RAS膜锚定重要性的现有数据，并对这一主要集中在预烯基化抑制的靶向范式进行了批判性评价。此外，我们从公开可用的数据库(https://depmap.org/repurposing/))中对与预烯基化相关的药物敏感性数据进行了RAS突变特异性分析，其中包括三类预烯基化抑制剂：他汀类药物、N-双膦酸类和法尼基转移酶抑制剂。我们观察到，根据KRAS突变状态和起源组织的不同，对N-双膦酸类和法尼基转移酶抑制剂的敏感性存在显著差异。这些观察结果强调了影响预烯基化抑制效果的因素的重要性，如不同KRAS突变的不同特征、组织特异性突变模式、K-RAS周转以及预烯基化过程调节的变化。最后，我们列出了可能导致临床前研究和临床研究结果之间巨大差异的因素，包括方法学上的缺陷，对K-RAS蛋白周转的不完全了解，以及KRAS突变肿瘤中KRAS依赖性的变化。
KRAS is one of the most commonly mutated oncogene and a negative predictive factor for a number of targeted therapies. Therefore, the development of targeting strategies against mutant KRAS is urgently needed. One potential strategy involves disruption of K-Ras membrane localization, which is necessary for its proper function. In this review, we summarize the current data about the importance of membrane-anchorage of K-Ras and provide a critical evaluation of this targeting paradigm focusing mainly on prenylation inhibition. Additionally, we performed a RAS mutation-specific analysis of prenylation-related drug sensitivity data from a publicly available database (https://depmap.org/repurposing/) of three classes of prenylation inhibitors: statins, N-bisphosphonates, and farnesyl-transferase inhibitors. We observed significant differences in sensitivity to N-bisphosphonates and farnesyl-transferase inhibitors depending on KRAS mutational status and tissue of origin. These observations emphasize the importance of factors affecting efficacy of prenylation inhibition, like distinct features of different KRAS mutations, tissue-specific mutational patterns, K-Ras turnover, and changes in regulation of prenylation process. Finally, we enlist the factors that might be responsible for the large discrepancy between the outcomes in preclinical and clinical studies including methodological pitfalls, the incomplete understanding of K-Ras protein turnover, and the variation of KRAS dependency in KRAS mutant tumors.
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