Emerging strategies to target RAS signaling in human cancer therapy

<jats:title>Abstract</jats:title><jats:p><jats:italic>RAS</jats:italic>mutations (<jats:italic>HRAS</jats:italic>,<jats:italic>NRAS</jats:italic>, and<jats:italic>KRAS</jats:italic>) are among the most common oncogenes, and around 19% of patients with cancer harbor<jats:italic>RAS</jats:italic>mutations. Cells harboring<jats:italic>RAS</jats:italic>mutations tend to undergo malignant transformation and exhibit malignant phenotypes. The mutational status of<jats:italic>RAS</jats:italic>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<jats:italic>RAS</jats:italic>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 KRAS<jats:sup>G12C</jats:sup>-mutant NSCLC patients. Therefore, here we fully review<jats:italic>RAS</jats:italic>mutations in human cancer and especially focus on emerging strategies that have been recently developed for RAS-targeting therapy.</jats:p>