PIK3CA and neoplasm: Phosphatidylinositol 3-kinase (PI3K) is one of the main effector RAS pathways, and the RAS-PI3K interaction is vital in RAS-driven tumorigenesis, tumor maintenance, and metastasis.37 Due to structural perturbation, G12R upregulates KRAS-independent PI3K activity directly, unlike the more common G12, G12D, or G12V variants in PDAC.38 The defective PI3Kα signaling in G12R compared with other G12 mutations in PDAC may impact the drivers of resistance to KRAS inhibitors and may ultimately require different therapeutic approaches.