Ting Tian, Wangping Li
• This article highlights the research progress and clinical trial results of KRAS G12C targeted inhibitors. • The resistance mechanism and research progress of KRAS G12C targeted inhibitors are described. • Combination treatment strategies and novel therapies for KRAS G12C -mutant NSCLC. Lung cancer has an extremely high mortality rate among malignant tumors, posing a significant threat to human health Among all lung cancer cases, non-small cell lung cancer (NSCLC) accounts for a significant proportion and has become a hot topic in clinical research and treatment. The Kirsten rat sarcoma viral oncogene homolog ( KRAS ) is one of the most common oncogenic drivers in NSCLC, closely associated with tumor initiation, treatment response, and prognosis. However, due to the relatively smooth surface of the KRAS protein and the lack of drug-binding pockets, it has long been regarded as an "undrugable target". With further research, recently, targeted drugs targeting the KRAS G12C gene mutation have achieved significant breakthroughs in clinical trials, especially the application of KRAS G12C -specific inhibitors adagrasib and sotorasib, which has changed the treatment landscape for NSCLC patients. To address challenges such as tumor heterogeneity, the complexity of the tumor microenvironment, interpatient variability, and acquired drug resistance mechanisms, combination therapy strategies involving KRAS G12C inhibitors have emerged sequentially. This article systematically reviews the progress of targeted therapy for KRAS G12C -mutant NSCLC and the results of related clinical trials, while exploring novel therapeutic strategies for patients with KRAS G12C mutations, aiming to provide a reference for the selection of clinical treatment regimens.