Pancreatic cancers treated with daraxonrasib can escape through multiple, often simultaneous routes, according to the first systematic analysis of resistance to Revolution Medicines' multi-selective RAS inhibitor — but the study also identified combination strategies capable of shutting down several of those escape routes in preclinical models. Published August 12 in Nature Medicine, the study, carried out by Revolution Medicines and Dana-Farber Cancer Institute, analyzed tumor evolution in patients with RAS-mutant metastatic PDAC treated with daraxonrasib (RMC-6236), alongside cellular and animal models designed to reproduce and interrogate the resistance mechanisms.
The findings arrive at a pivotal point for daraxonrasib, with Revolution last month beginning an NDA filing after the drug nearly doubled overall survival versus chemotherapy in the Phase III RASolute 302 trial (NCT06577571) in previously treated metastatic PDAC. Understanding how resistance emerges before the drug reaches wider clinical use could give the field an opportunity to design combination regimens prospectively rather than reactively.
Heterogeneous, polyclonal resistance
In the study, circulating tumor DNA (ctDNA) profiling using an 800-plus gene panel from Guardant Health was performed on paired pre- and post-treatment samples from 44 patients with RAS-mutant metastatic PDAC enrolled on the Phase I/II monotherapy trial (NCT05379985). The authors reported that resistance was both heterogeneous and polyclonal — multiple co-occurring mechanisms were detected within individual patients, with no single alteration dominating.
On-target mechanisms, meaning those that reactivate RAS signaling directly, were predominant and included secondary NRAS and HRAS switching mutations and KRAS amplification, identified in approximately 36% of patients. Off-target mechanisms included ERBB2 (HER2) amplification, MET amplification, EGFR alterations, and Hippo/YAP pathway changes. Notably, the researchers detected no secondary KRAS point mutations in the PDAC cohort, contrasting with resistance patterns reported for covalent KRAS G12C inhibitors such as Lumakras (sotorasib) and Krazati (adagrasib). Instead, resistance frequently involved alterations elsewhere in the RAS network or activation of alternative signaling pathways.
Mechanism and preclinical validation
Daraxonrasib works as a molecular glue, recruiting cyclophilin A to active, GTP-bound RAS to form a ternary complex that prevents RAS from engaging downstream effectors. Unlike mutation-selective KRAS inhibitors, it is designed to inhibit active KRAS, NRAS and HRAS across multiple RAS variants.