RAS Signaling Targeted Cancer Therapy

Mutated and activated RAS is a key oncogene that drives various human cancers. RAS-targeted therapy has been an extensive research focus but has made little progress given its long history. Several novel binding sites, especially the Cys12 mutation in KRAS G12C, have been identified, paving the way for irreversible inhibitor development. A series of clinical trials have proven their efficacies, and the first RAS G12C-targeting drug sotorasib (AMG-510) received approval for non-small cell lung cancer treatment in May, 2021. In another approach, the development of indirect RAS inhibitors that target components of the RAS signaling pathway, including the upstream enzyme farnesyl transferase and the downstream effector molecules SOS1, MEK, AKT, and SHP2, has also made significant progress. This review systematically summarizes the latest progress in RAS signaling pathway-targeted drugs, discusses clinical challenges, and proposes beneficial strategies for RAS-targeted therapy.