Targeting RAS-Addicted Cancers with RAS(ON) Tri-Complex Inhibitors

Hear how Revolution Medicines has built a portfolio of novel inhibitors that are tailored to bind to different RAS(ON) proteins. Targeting RAS-Addicted Cancers with RAS(ON) Tri-Complex Inhibitors * * * * * RAS is a molecular switch that toggles between an inactive GDP bound (OFF) state and an active GTP-bound (ON) state. Accumulation of RAS(ON) in tumor cells drives uncontrolled RAS pathway activation and growth in RAS mutant cancers. RAS(ON) proteins have been amongst the most notoriously undruggable targets in cancer due in large part to their typically smooth, featureless surface. The tri-complex platform is inspired by one of nature’s solutions to modulating complex cellular targets. Tri-complex inhibitors bind to the chaperone protein cyclophilin A to create a novel interface with high affinity for RAS(ON) proteins. Using structure-guided design, the resulting inhibitory tri-complexes can be tailored to bind to different RAS(ON) proteins, including those with oncogenic mutations at each of the three most commonly mutated hotspots - G12, G13 and Q61. Using this approach, Revolution Medicines has built a portfolio of novel RAS(ON) inhibitors, with diverse and complementary selectivity profiles, all targeting the active state of RAS. Daraxonrasib is an oral, RAS(ON) multi-selective, tri-complex inhibitor designed to target cancers driven by multiple common RAS genotypes. RASONQUE (daraxonrasib) received FDA approval in August 2026 for the treatment of adults with metastatic pancreatic ductal adenocarcinoma (PDAC) who have received at least one prior systemic therapy or who are not candidates for multiagent systemic therapy. Dr. Smith will describe the preclinical and clinical development of daraxonrasib and related RAS(ON) tri-complex inhibitors in the pipeline at Revolution Medicines for RAS-driven cancers.