Emerging Strategies for KRAS Inhibition in Cancer: From G12C to Pan-RAS and Beyond

Kirsten RAS oncogene (KRAS) is the most frequently mutated oncogene in human cancer and has historically been considered “undruggable”. The development of covalent KRASG12C inhibitors has marked a paradigm shift, leading to the first approved direct Rat Sarcoma Virus (RAS)-targeted therapies in non-small cell lung cancer. However, their clinical benefit is often transient due to intrinsic and acquired resistance, and no targeted therapies are yet approved for other prevalent KRAS variants such as G12D and G12V. This review is intended for clinicians and translational researchers with an interest in precision oncology and early-phase drug development, and summarises recent advances in the field, including next-generation allele-specific inhibitors, pan-KRAS and pan-RAS inhibitors, KRAS degraders, indirect strategies targeting upstream regulators, and emerging immunologic approaches. We also outline rational combination strategies designed to prevent pathway reactivation, overcome tumor heterogeneity, and improve the depth and durability of response. Take together, these developments illustrate both the progress and the persistent challenges in targeting KRAS-mutant cancers. By integrating clinical trial data with mechanistic insights from preclinical studies, this review provides an updated perspective on the opportunities and limitations of KRAS-directed therapies and their broader implications for the future of precision oncology.