RAS-targeted therapies: is the undruggable drugged?-猫眼课题宝

DOI：

10.1038/s41573-020-0068-6

发表时间：

2020-08

期刊：

Nature reviews. Drug discovery

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

Moore AR;Rosenberg SC;McCormick F;Malek S

来源链接：

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809886/

RAS（KRAS、NRAS和HRAS）是癌症中最常发生突变的基因家族，因此，研究人员三十多年来一直在寻找一种有效的RAS抑制剂。甚至在10年前，RAS抑制剂还如此难以捉摸，以至于RAS被称为“无药可治”。现在，随着针对非小细胞肺癌中最常突变的RAS版本KRASG12C的等位基因特异性共价抑制剂取得成功，我们有机会评估治疗RAS驱动癌症的最佳治疗策略。突变特异性的生化特性以及起源组织可能会影响此类治疗的效果。目前，通过等位基因特异性抑制剂直接抑制突变型RAS提供了最佳的治疗方法。针对RAS激活途径或RAS效应途径的疗法可以与这些直接的RAS抑制剂、免疫检查点抑制剂或T细胞靶向方法相结合，以治疗RAS突变肿瘤。在此，我们回顾了针对突变型RAS蛋白的疗法的最新进展，并讨论了这些疗法未来面临的挑战，包括联合治疗策略。

RAS (KRAS, NRAS and HRAS) is the most frequently mutated gene family in cancers, and, consequently, investigators have sought an effective RAS inhibitor for more than three decades. Even 10 years ago, RAS inhibitors were so elusive that RAS was termed ‘undruggable’. Now, with the success of allele-specific covalent inhibitors against the most frequently mutated version of RAS in non-small-cell lung cancer, KRASG12C, we have the opportunity to evaluate the best therapeutic strategies to treat RAS-driven cancers. Mutation-specific biochemical properties, as well as the tissue of origin, are likely to affect the effectiveness of such treatments. Currently, direct inhibition of mutant RAS through allele-specific inhibitors provides the best therapeutic approach. Therapies that target RAS-activating pathways or RAS effector pathways could be combined with these direct RAS inhibitors, immune checkpoint inhibitors or T cell-targeting approaches to treat RAS-mutant tumours. Here we review recent advances in therapies that target mutant RAS proteins and discuss the future challenges of these therapies, including combination strategies.