Abstract
Kirsten rat sarcoma viral oncogene homolog (KRAS), a member of the small GTPase family, is the most frequently mutated RAS isoform in human cancers. It drives tumorigenesis and progression in various malignancies, including pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), and colorectal cancer (CRC), and has long been considered an "undruggable" target. Recent advances in mutant-selective KRAS inhibition have reshaped this view, but therapeutic responses remain limited by adaptive resistance, tumor heterogeneity, and context-dependent signaling dependencies. This review focuses on how allele-specific biochemical properties, tissue context, and co-mutational backgrounds shape KRAS signaling output, tumor progression, therapeutic response, and resistance. We further discuss current diagnostic approaches and therapeutic strategies, ranging from direct mutant-selective inhibitors to pathway-targeted combinations, degraders, immunotherapies, RNA-based approaches, and exosome-mediated delivery. Finally, we highlight key challenges including adaptive resistance, tumor heterogeneity, allele-specific druggability, and the need for biomarker-guided combination strategies. Together, this review provides a framework for understanding KRAS-mutant cancers as biologically diverse diseases and for guiding the development of more precise and durable therapeutic strategies.