KRAS mutations in Non-Small Cell Lung Cancer: translational aspects, current therapies and challenges for future research

Mutations in the KRAS gene are prominent oncogenic drivers in non-small cell lung cancer (NSCLC), with multiple pathophysiological, clinical and prognostic implications. Although historically considered an "undruggable" target, recent research led to the development of specific KRAS-G12C inhibitors, like sotorasib and adagrasib which are currently approved for clinical use in patients affected by advanced NSCLC. However, the clinical utility of these drugs is often limited by resistance development through several biological mechanisms, including additional KRAS mutations, activation of compensatory pathways and metabolic reprogramming. In addition, the immunosuppressive tumor microenvironment (TME) in KRAS-mutant NSCLC reduces the efficacy of immune checkpoint inhibitors (ICIs), further complicating treatment and clinical outcomes. Combination therapy with KRAS inhibitors, ICIs, and other agents appears currently as an attractive option for overcoming resistance and improving survival in these patients. This review provides a detailed overview of KRAS genetic alterations in NSCLC, focusing on the involved molecular pathways, current and potential targeted therapies, challenges related to tumor heterogeneity, as well as ongoing research and future perspectives. In addition, the role of TME in generating treatment resistance is discussed, along with emerging therapeutic options that target non-G12C KRAS mutations or combine different pharmacological approaches to disrupt both oncogenic signaling and immune evasion.