Disrupted molecular glue complex drives RAS inhibitor resistance
Summary
Tri-complex inhibitors (TCIs) are molecular glues that bind the active, guanosine triphosphate (GTP)-bound state of RAS and recruit cyclophilin A (CYPA) to form a synthetic complex that blocks oncogenic signaling. Although these agents have shown clinical activity in RAS mutant cancers, resistance mechanisms remain poorly defined. Here, we analyzed paired baseline and end-of-treatment samples from 40 patients treated with the RAS inhibitor daraxonrasib and identified recurrent alterations
Content
# Disrupted molecular glue complex drives RAS inhibitor resistance
*Published: 2026 May 14*
Tri-complex inhibitors (TCIs) are molecular glues that bind the active,
guanosine triphosphate (GTP)-bound state of RAS and recruit cyclophilin A (CYPA)
to form a synthetic complex that blocks oncogenic signaling. Although these
agents have shown clinical activity in RAS mutant cancers, resistance mechanisms
remain poorly defined. Here, we analyzed paired baseline and end-of-treatment
samples from 40 patients treated with the RAS inhibitor daraxonrasib and
identified recurrent alterations in 18 cases. Structural and functional analyses
revealed that acquired mutations confer resistance by disrupting interactions
essential for daraxonrasib binding to RAS, including RAS Y64 mutations, or by
enhancing the RAS-RAF interaction, thereby favoring native RAS-RAF signaling,
including RAS Y71 or kinase-dead/hypoactive BRAF mutations. We then identified a
TCI that targets RAS Y64 mutants and combination therapies to target resistance
driven by kinase-dead BRAF. These findings uncover convergent resistance
mechanisms that undermine the molecular glue function and offer a mechanistic
blueprint for enhancing therapeutic efficacy in RAS-driven malignancies.
DOI: 10.1016/j.cell.2026.03.031