KRAS is the most frequently altered oncogenic driver in human cancer. Its mutations drive the initiation and progression of many solid tumors. Clinical validation of covalent KRASG12C inhibitors marked a step change and renewed focus on allele-directed strategies and the circuits that regulate KRAS signaling. We summarize recent advances across KRAS structure and conformations, allelic heterogeneity, and roles in signaling, metabolic control, and immune microenvironment remodeling. For direct inhibition, we summarize allele-specific drugs for G12C, G12D and G12V, as well as conformation-selective broad-spectrum inhibitors, outlining design logic and therapeutic outlook. For indirect intervention, we analyze SHP2 and SOS1 inhibition, MEK blockade, metabolic targeting, and immunotherapy combinations, with the biological rationale for each pairing. We also analyze the genetic and phenotypic mechanisms underlying primary and acquired resistance, and discuss counterstrategies such as next-generation inhibitors, rational treatment sequencing, and circulating tumor DNA (ctDNA) monitoring. The KRAS therapeutic landscape is shifting toward conformation-aware, multimodal precision therapy and longitudinal disease management, which providing avenues for durable control of KRAS-mutant tumors.
Liang et al. (Fri,) studied this question.