RAS-targeted therapies: is the undruggable drugged?

赫拉 神经母细胞瘤RAS病毒癌基因同源物 克拉斯 癌症研究 靶向治疗 计算生物学 癌症 效应器 合成致死 突变 医学 突变体 生物 生物信息学 基因 遗传学 免疫学
作者
Amanda R. Moore,Scott Rosenberg,Frank McCormick,Shiva Malek
出处
期刊:Nature Reviews Drug Discovery [Springer Nature]
卷期号:19 (8): 533-552 被引量:725
标识
DOI:10.1038/s41573-020-0068-6
摘要

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. RAS proteins, which are frequently altered in cancer, were once considered undruggable, but compounds targeting some mutant RAS proteins have recently demonstrated clinical efficacy. In this Review, Malek and colleagues explore how these and other drugs that target RAS or associated pathways might be used effectively, particularly in combinations, and discuss other RAS-targeted therapies in the pipeline.
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