RAS mutations (HRAS, NRAS, and KRAS) are among the most common oncogenes, and around 19% of patients with cancer harbor RAS mutations. Cells harboring RAS mutations tend to undergo malignant transformation and exhibit malignant phenotypes. The mutational status of RAS correlates with the clinicopathological features of patients, such as mucinous type and poor differentiation, as well as response to anti-EGFR therapies in certain types of human cancers. Although RAS protein had been considered as a potential target for tumors with RAS mutations, it was once referred to as a undruggable target due to the consecutive failure in the discovery of RAS protein inhibitors. However, recent studies on the structure, signaling, and function of RAS have shed light on the development of RAS-targeting drugs, especially with the approval of Lumakras (sotorasib, AMG510) in treatment of KRASG12C-mutant NSCLC patients. Therefore, here we fully review RAS mutations in human cancer and especially focus on emerging strategies that have been recently developed for RAS-targeting therapy.

中文翻译：

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人类癌症治疗中针对 RAS 信号传导的新兴策略


RAS 突变（HRAS、NRAS 和 KRAS）是最常见的癌基因之一，约 19% 的癌症患者存在 RAS 突变。携带 RAS 突变的细胞往往会发生恶性转化并表现出恶性表型。 RAS 的突变状态与患者的临床病理特征相关，例如粘液型和低分化，以及某些类型人类癌症对抗 EGFR 治疗的反应。尽管RAS蛋白曾被认为是RAS突变肿瘤的潜在靶点，但由于RAS蛋白抑制剂的发现连续失败，一度被称为不可成药靶点。然而，最近对 RAS 结构、信号传导和功能的研究为 RAS 靶向药物的开发提供了线索，特别是 Lumakras（sotorasib，AMG510）被批准用于治疗 KRASG12C 突变 NSCLC 患者。因此，我们在这里全面回顾人类癌症中的 RAS 突变，特别关注最近开发的 RAS 靶向治疗的新兴策略。