Decoding Resistance to KRAS Inhibitors in Pancreatic Cancer

A comprehensive study published in Cancer Discovery identifies key mechanisms behind resistance to promising KRAS-targeted therapies in pancreatic ductal adenocarcinoma (PDAC). Analyzing clinical samples and diverse preclinical models, researchers pinpointed genetic alterations (such as mutations in PIK3CA, amplifications of KRAS, MYC, MET, EGFR, and CDK6) and cellular processes (including epithelial-to-mesenchymal transition and activation of PI3K-AKT-mTOR pathways) that drive drug resistance. Importantly, the study also highlights differential therapeutic responses based on tumor cell states, revealing that mesenchymal and basal-like PDAC cells are more responsive to KRAS inhibition than classical epithelial cells. The authors demonstrate improved tumor control by combining KRAS inhibitors with chemotherapy, offering a promising path toward overcoming resistance and optimizing pancreatic cancer treatments.