Remodeling of the tumor/tumor microenvironment ecosystem during KRAS G12C inhibitor clinical resistance in lung cancer

KRAS G12C inhibitors such as sotorasib and adagrasib are often effective in KRAS G12C–driven non–small cell lung cancer (NSCLC) patients. However, acquired resistance limits long-term patient survival. In this issue of the JCI, Tsai et al. present a comprehensive genetic analysis of multiple tumors with acquired sotorasib resistance obtained through an autopsy of a patient with KRAS G12C–mutant NSCLC. This analysis of pre- and posttreatment tumors uncovered cancer cell–intrinsic and –extrinsic features of resistance, including reactivation of KRAS-mediated signaling, reprogramming of metabolism, epithelial-mesenchymal transition, and tumor microenvironment changes. This elegant study demonstrates the multifaceted nature of KRAS G12C inhibitor clinical resistance and potential avenues to overcome resistance.