Oncogenic RAS proteins, which are mutated in approximately 24% of all human cancers, have earned a well-deserved reputation as being “undruggable.” However, several studies have challenged that reputation. With the first small molecules that directly target one oncogenic RAS mutant (G12C) undergoing clinical evaluation, there have been substantial advances in finding anti-RAS therapeutic strategies. Furthermore, new insights have come from the growing appreciation that neither all RAS proteins (HRAS, NRAS, and KRAS4A/KRAS4B) nor all oncogenic RAS mutations (such as at residues Gly¹², Gly¹³, and Gln⁶¹) have the same impact on RAS signaling and function. The role of the nonmutated, wild-type RAS proteins in the context of mutant RAS is increasingly considered to be targetable, with reports of strategies that directly disrupt either the RAS interaction with activating guanine nucleotide exchange factors (GEFs) or receptor tyrosine kinase–mediated and GEF-dependent RAS activation (such as by targeting the scaffolding phosphatase SHP2). Last, the development of agents that target downstream effectors of RAS signaling has advanced substantially. In this review, we highlight some important trends in the targeting of RAS proteins in cancer.

致癌 RAS 蛋白在大约 24% 的人类癌症中发生突变，赢得了当之无愧的“不可抗药性”的美誉。然而，一些研究挑战了这种声誉。随着第一个直接靶向一种致癌 RAS 突变体 (G12C) 的小分子正在进行临床评估，在寻找抗 RAS 治疗策略方面取得了重大进展。此外，新的见解来自日益增长的认识，即所有 RAS 蛋白（HRAS、NRAS 和 KRAS4A/KRAS4B）和所有致癌 RAS 突变（例如残基 Gly ¹²、Gly ¹³和 Gln ⁶¹) 对 RAS 信令和功能有相同的影响。非突变的野生型 RAS 蛋白在突变 RAS 背景下的作用越来越被认为是可靶向的，有报道称直接破坏 RAS 与活化鸟嘌呤核苷酸交换因子 (GEF) 或受体酪氨酸激酶介导的相互作用的策略和 GEF 依赖性 RAS 激活（例如通过靶向支架磷酸酶 SHP2）。最后，针对 RAS 信号下游效应子的药物的开发取得了实质性进展。在这篇综述中，我们强调了在癌症中靶向 RAS 蛋白的一些重要趋势。