Targeting KRAS-Mutant Lung Cancers

KRAS mutations are the most common oncogenic driver alterations in non–small cell lung cancer (NSCLC) and define biologically heterogeneous diseases shaped by mutation subtype, co-mutation patterns, and immune contexture. Recent advances in structural and chemical biology have transformed KRAS from an undruggable target into a rapidly expanding therapeutic vulnerability. The first allele-specific inhibitors, sotorasib and adagrasib, validated KRAS G12C as a druggable dependency, changing the treatment paradigm for previously treated KRAS G12C NSCLC, although primary, acquired, and adaptive resistance remain widespread. Next-generation inhibitors such as divarasib improve potency and tolerability but continue to face resistance through secondary KRAS alterations, bypass receptor tyrosine kinase (RTK) signaling, and adaptive MAPK reactivation. These challenges have spurred the development of KRAS(ON) inhibitors, dual ON/OFF inhibitors, and broader pan- KRAS and pan- RAS agents capable of targeting multiple oncogenic variants, including G12D, G12V, G12X, G13X, and Q61X. Early clinical results with tricomplex RAS(ON) inhibitors (eg, daraxonrasib) and G12D-selective agents (eg, zoldonrasib) demonstrate promising activity in subsets historically lacking targeted options. In parallel, rational combination strategies aimed at enhancing overall efficacy, such as RTK, SHP2/SOS1, or PD-1/PD-L1 blockade, together with emerging modalities including RAF–MEK clamps, adoptive cell therapies, and KRAS vaccines, are broadening the therapeutic landscape. This review comprehensively summarizes KRAS biology, therapeutic advances, mechanisms of resistance, and emerging strategies that are reshaping the treatment landscape of KRAS -mutant NSCLC.