[Targeting KRAS-Mutant Cancers-Therapeutic Strategies and Mechanisms of Resistance to RAS Inhibitors]

KRAS mutations represent one of the most prevalent oncogenic alterations, occurring in approximately 20% of human cancers. Although KRAS had long been regarded as"undruggable,"the identification of a druggable pocket has catalyzed rapid progress in the development of targeted therapeutics. To date, the only approved KRAS-directed agent in Japan is sotorasib, a GDP-state inhibitor specific for the KRAS G12C mutation. However, a diverse array of next-generation strategies-including pan-KRAS inhibitors, pan-RAS inhibitors, tri-complex inhibitors, and targeted protein degradation modalities-are currently under active investigation. These advances have drawn increasing attention to the functional heterogeneity and differential druggability among distinct KRAS mutation subtypes, as well as organ-specific biological differences that had previously received limited consideration. Moreover, as with other molecularly targeted therapies, multiple resistance mechanisms to KRAS inhibition have been reported, underscoring the need for therapeutic strategies capable of overcoming or preventing treatment resistance.