Precision Targeting of KRAS-Mutant Cancers: Beyond G12C Toward G12D and Pan-RAS Therapeutic Strategies

KRAS is one of the most frequently mutated oncogenes in human cancer and has long been considered an “undruggable” therapeutic target because of its high affinity for guanine nucleotides and limited druggable binding pockets. Recent advances in structural biology and molecular pharmacology have transformed this paradigm, leading to the successful development of KRAS G12C inhibitors such as sotorasib and adagrasib. These agents established proof-of-concept for direct KRAS inhibition and marked an important advance in precision oncology. However, intrinsic and acquired resistance mechanisms, adaptive signaling reactivation, and tumor heterogeneity continue to limit the durability of clinical responses. Therapeutic development has rapidly expanded beyond KRAS G12C toward broader strategies including KRAS G12D inhibitors, pan-RAS and RAS(ON) inhibitors, degraders, and biomarker-guided combination approaches. In parallel, circulating tumor DNA (ctDNA) and other biomarker-driven strategies are increasingly enabling dynamic monitoring of treatment response, minimal residual disease, and resistance evolution. In this review, we summarize the molecular biology and conformational regulation of KRAS signaling, recent advances in allele-specific and pan-RAS therapeutic strategies, mechanisms of resistance, and emerging precision oncology frameworks for KRAS-mutant cancers.