KRAS inhibition in non–small cell lung cancer: Past failures, new findings and upcoming challenges.

Despite the high prevalence of Kirsten rat sarcoma (KRAS) mutations in non-small cell lung cancer (NSCLC), for a long time it has been defined as an 'undruggable target', with precision medicine not considered as an adequate approach to treat this subgroup of patients. After several years of efforts, preliminary data from early clinical trials have recently demonstrated that direct pharmacological inhibition of KRAS p.G12C mutation is possible, emerging as an effective targeted treatment for about 10–12% of patients with advanced NSCLC, with potential relevant impact on their long-term survival and quality of life. This review reports the current status of KRAS mutations detection in the Italian real-word scenario, summarises the biological basis of KRAS inhibition in NSCLC and provides an updated overview of therapeutic strategies, discussing the potential reasons for past failures and analysing the upcoming challenges related to the advent of new targeted agents in clinical practice. • Kirsten rat sarcoma (KRAS) p.G12C mutations characterise about 10–12% of lung adenocarcinoma. • KRAS p.G12C mutation is now considered as a druggable target in non–small cell lung cancer. • KRAS p.G12C small-molecule inhibitors are emerging as an effective treatment option for metastatic disease. • Combinations with the Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) or immunotherapy represent promising therapeutic strategies. • Molecular and biological heterogeneity represent major challenges for clinical lung cancer research. [ABSTRACT FROM AUTHOR]