Unraveling Resistance to KRAS Inhibition in Pancreatic Cancer

KRAS inhibitors have shown promise in treating pancreatic ductal adenocarcinoma (PDAC), yet resistance frequently diminishes their long-term effectiveness. This study delves into both genetic and non-genetic mechanisms driving resistance to KRASG12C and KRASG12D inhibitors like adagrasib, sotorasib, and MRTX1133. Findings reveal that mutations and amplifications in pathways like PIK3CA, MYC, and PI3K-AKT-mTOR, as well as epithelial-to-mesenchymal transition, underlie resistance. In advanced mouse and organoid models, drug resistance evolved alongside adaptive transcriptional programs. Interestingly, mesenchymal and basal-like tumor states showed better responses than classical states, and combining KRAS inhibitors with chemotherapy significantly improved tumor control. These insights emphasize the need for multi-modal treatment strategies to enhance the efficacy and sustainability of KRAS-targeted therapies in PDAC.