Tumor suppressor genes and KRAS G12C inhibitor resistance in non-small cell lung cancer

KRAS G12C inhibitors (G12Cis) have revolutionized the treatment of cancers driven by this historically undruggable mutation, offering unprecedented clinical responses in non-small cell lung cancer (NSCLC) and other malignancies. However, both primary and acquired resistance rapidly curtail their efficacy. Emerging clinical and preclinical evidence underscores the heterogeneity of resistance mechanisms. Strikingly, in KRAS-driven NSCLC, a common phenomenon is co-mutations in tumor suppressor genes (TSGs), which orchestrate resistance through multifaceted pathways such as sustained proliferation, metabolic reprogramming, phenotypic plasticity, and immune microenvironment remodeling. Accordingly, this review summarizes relevant reasons underlying diverse resistant mechanisms in KRAS G12C-mutated NSCLC, with an emphasis on deciphering the mechanism of tumor suppressor gene (TSG) alterations serving as key mediators linking oncogenic KRAS dependency to therapeutic resistance. Our research continued to discuss relevant preclinical models to facilitate the advancement of the study of these resistance mechanisms.