Current Landscape of RAS-Targeted Therapy for Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) continues to carry a poor prognosis, and only incremental gains in systemic therapy have been made over the past decade. Because activating KRAS mutations are present in more than 90% of PDAC and serve as the inciting oncogenic driver, RAS has long been a coveted but elusive therapeutic target, historically deemed "undruggable." Allele-specific KRASG12C inhibitors provided the first proof of concept, but G12C mutations account for only about 1% of PDAC, in which G12D, G12V, and G12R predominate. Recent advances in the structural and biochemical understanding of RAS have yielded a rapidly expanding therapeutic landscape, broadly comprising non-G12C allele-specific inhibitors, pan-RAS and pan-KRAS inhibitors, and proteolysis-targeting chimeras. This progress is exemplified by the phase III RASolute-302 trial, in which the RAS(ON) multi-selective tri-complex inhibitor daraxonrasib nearly doubled overall survival versus chemotherapy in previously treated metastatic PDAC (13.2 vs 6.7 months), positioning it to become the first broadly applicable RAS-targeted therapy in this disease. Here we review the biology of RAS, the mechanistic rationale and clinical data behind emerging RAS-directed agents, and the central challenges ahead: targeting different KRAS subtypes, managing distinct toxicities, and overcoming the genetic and non-genetic resistance mechanisms that will require rational combination strategies to translate these gains into durable benefit.