From "Undruggable" to Actionable: RAS(ON) Inhibition and the Emerging Therapeutic Landscape of Pancreatic Cancer

Activating mutations in RAS genes, overwhelmingly KRAS at codon 12, occur in more than 90% of pancreatic ductal adenocarcinomas (PDAC), yet for four decades RAS stood as the emblem of undruggability. This Perspective traces the reasoning that carried the field from failed indirect strategies, through the allele-restricted success of covalent KRAS G12C inhibitors, to agents that engage the active, GTP-bound conformation of RAS irrespective of the mutant residue. The oral multiselective RAS(ON) inhibitor daraxonrasib (RMC-6236) embodies this shift: a tri-complex, molecular-glue agent that recruits cyclophilin A to occlude the effector-binding surface of RAS-GTP across mutant and wild-type isoforms. In the phase 3 RASolute-302 trial in metastatic PDAC progressing after one prior systemic therapy, daraxonrasib produced a median overall survival of 13.2 months versus 6.7 months with physician's-choice chemotherapy (hazard ratio for death, 0.40), with concordant gains in progression-free survival and objective response rate, and on August 26, 2026, it became the first RAS-directed therapy approved for pancreatic cancer. The approval is best understood not simply as a new second-line option but as clinical validation of active-state RAS targeting as a generalizable pharmacological strategy. The supporting evidence nonetheless has defined boundaries: the trial addressed post-progression metastatic disease only, follow-up remains immature, the signal in non-G12 tumors rests on a small subgroup with discordant outcomes, and acquired resistance is dominated by reactivation of RAS-pathway signaling rather than secondary KRAS mutations. The undruggable-RAS era has closed in its strongest form; the durability, optimal combinations, and reach of RAS(ON) inhibition across lines of therapy and tumor types remain open questions.