Targeting KRAS in Solid Tumors: Current Challenges and Future Opportunities of Novel KRAS Inhibitors.
Targeting KRAS in Solid Tumors: Current Challenges and Future Opportunities of Novel KRAS Inhibitors.
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在实体肿瘤中靶向KRAS：新型KRAS抑制剂的当前挑战和未来机遇。
DOI：
10.3390/pharmaceutics13050653
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发表时间：
2021-05-04
期刊：
影响因子：
5.4
通讯作者：
Grossi F
中科院分区：
文献类型：
--
作者：
Indini A;Rijavec E;Ghidini M;Cortellini A;Grossi F
RAS家族蛋白的激活突变在所有人类癌症的约25%中发现。不同的实体瘤与某些RAS亚型的突变相关，Kirsten RAS（KRAS）是最常见的突变亚型。历史上，KRAS被认为是“不可用药的”，主要是因为RAS蛋白似乎不存在小抑制分子可以结合的合适口袋。然而，随着新型KRAS抑制剂的出现，这种情况在过去几年中发生了变化。在这篇综述中，我们描述了KRAS突变在不同实体瘤中的作用，提供了目前正在开发的新型KRAS抑制剂的数据以及该领域正在进行的研究的最新概述。进行了文献检索，以选择关于KRAS突变实体瘤中KRAS抑制策略的论文、摘要和口头报告。总体而言，靶向KRAS G12C的分子获得了最有希望的治疗结果，从而为非小细胞肺癌的显著治疗改善铺平了道路。不幸的是，KRAS G12C突变在其他实体瘤中相当罕见，即胰腺导管腺癌和结直肠癌。目前正在临床试验中评估几种组合策略，以绕过导致突变KRAS对迄今为止采用的主要治疗策略产生内在抗性的抗性机制。结果表明，KRAS的治疗方案已经开始改变，进一步的研究将在这一领域带来治疗结果。
Activating mutations in RAS family proteins are found in ~25% of all human cancers. Different solid tumors are correlated with mutations in certain isoforms of RAS, with Kirsten RAS (KRAS) being the most frequently mutated isoform. Historically, KRAS has been acknowledged as “undruggable”, largely because the RAS proteins do not appear to present suitable pockets to which small inhibitory molecules can bind. However, this scenario has changed over the last years with the advent of novel KRAS inhibitors. In this review, we describe the role of KRAS mutation across different solid tumors, providing data on novel KRAS inhibitors currently under development and an updated overview of ongoing research in this field. A literature search was performed to select papers, abstracts, and oral presentation on KRAS inhibitory strategies in KRAS mutated solid tumors. Overall, the most promising therapeutic results have been obtained with molecules targeting KRAS G12C, thus paving the way for a significant therapeutic improvement in non-small cell lung cancer. Unfortunately, KRAS G12C mutation is rather uncommon in other solid tumors, namely pancreatic ductal adenocarcinoma and colorectal cancer. Several combination strategies are currently under evaluation in clinical trials, in order to bypass the resistance mechanisms responsible for the intrinsic resistance of mutated KRAS to the main therapeutic strategies adopted to date. Results suggest that the therapeutic scenario of KRAS has started to change, and further research will bring therapeutic results in this field.
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