Research progress of direct and indirect KRAS-targeting protein degraders in KRAS-mutant cancers

The RAS gene, being the most frequently activated proto-oncogene, belongs to the GTPase family. Its primary physiological function is to regulate cell proliferation. The main members of the RAS gene are H-RAS, K-RAS, and N-RAS. Approximately 16 % of human cancers are related to RAS proteins. KRAS is the most common oncogene. About 17 % of solid tumors have KRAS mutations, which account for around 50 %, 80 %, and 25 % of colorectal cancer, pancreatic cancer, and lung adenocarcinoma, respectively. Currently, significant advances have been made in the development of small-molecule inhibitors targeting KRAS mutants, with research efforts remaining actively ongoing across the field. In recent years, alongside the rapid advancement of targeted protein degradation (TPD) technology, studies on proteolysis targeting chimeras (PROTACs) tailored for KRAS have emerged sequentially in the academic literature, reflecting a growing focus on this therapeutic strategy. This provides a new way to address the issue of resistance caused by KRAS small molecule inhibitors. In this review, we summarize key recent advancements in the development of KRAS-targeting PROTACs, with a distinct focus on direct KRAS-targeting degraders-specifically their major subtypes: one that binds directly to KRAS mutant variants (e.g., G12C, G12D), and the other being pan-KRAS degraders. Concurrently, we extend our discussion to indirect KRAS-targeting degraders, which do not directly bind KRAS but modulate its signaling activity or protein stability by targeting upstream/downstream regulatory proteins in the KRAS pathway (e.g., SOS1, FAK, AKT).