Recent advances in targeted degradation in the RAS pathway

RAS (rat sarcoma) is one of the most frequently mutated gene families in cancer, encoding proteins classified as small GTPases. Mutations in RAS proteins result in abnormal activation of the RAS signaling pathway, a key driver in the initiation and progression of various malignancies. Consequently, targeting RAS proteins and the RAS signaling pathway has become a critical strategy in anticancer therapy. While RAS was historically considered an "undruggable" target, recent breakthroughs have yielded inhibitors specifically targeting KRASG12C and KRASG12D mutations, which have shown clinical efficacy in patients. However, these inhibitors face limitations due to rapid acquired resistance and the toxic effects of combination therapies in clinical settings. Targeted protein degradation (TPD) strategies, such as PROTACs and molecular glues, provide a novel approach by selectively degrading RAS proteins, or their upstream and downstream regulatory factors, to block aberrant signaling pathways. These degraders offer a promising alternative to traditional inhibitors by potentially circumventing resistance and enhancing therapeutic precision. This review discusses recent advancements in RAS pathway degraders, with an emphasis on targeting RAS mutations as well as their upstream regulators and downstream effectors for potential cancer treatments.