Disrupted molecular glue complex drives RAS inhibitor resistance

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Tri-complex inhibitors (TCIs) are molecular glues targeting the GTP-bound RAS state.
• TCIs recruit cyclophilin A (CYPA) to form a complex, inhibiting oncogenic signaling.
• Clinical activity of TCIs in RAS-mutant cancers is observed, but resistance mechanisms are not well understood.

Purpose of the Study:

• To investigate resistance mechanisms to the RAS inhibitor daraxonrasib in patients with RAS-mutant cancers.
• To identify specific genetic alterations conferring resistance to TCIs.
• To develop strategies to overcome TCI resistance.

Main Methods:

• Analysis of paired patient samples (baseline and end-of-treatment) from 40 patients treated with daraxonrasib.
• Structural and functional analyses of identified mutations.
• Identification of novel TCIs and combination therapies.

Main Results:

• Recurrent resistance alterations were identified in 18 out of 40 patients.
• Mutations in RAS (Y64) disrupted inhibitor binding.
• Mutations in RAS (Y71) or BRAF (kinase-dead) enhanced RAS-RAF signaling, conferring resistance.
• A TCI targeting RAS Y64 mutants was identified.
• Combination therapies for kinase-dead BRAF-driven resistance were proposed.

Conclusions:

• Convergent resistance mechanisms undermine TCI efficacy by disrupting molecular glue function.
• Targeting specific RAS and BRAF mutations is crucial for overcoming resistance.
• The findings provide a blueprint for enhancing therapeutic strategies in RAS-driven malignancies.