Disrupted molecular glue complex drives RAS inhibitor resistance

  • Cell. 2026 May 14;189(10):2918-2933.e17. doi: 10.1016/j.cell.2026.03.031.
Ben Sang  1 ,  Ling Feng Ye  2 ,  Zheng Fu  1 ,  Yasin Pourfarjam  1 ,  Antonio Cuevas-Navarro  1 ,  Shijie Fan  1 ,  Feng Hu  1 ,  Aaliyah Washington  1 ,  Diego J Rodriguez  3 ,  Alberto Vides  1 ,  Sumit Kar  4 ,  Ethan Ahler  4 ,  Kevin K Lin  4 ,  Aparna Hegde  4 ,  Jacqueline A M Smith  4 ,  Brian M Wolpin  5 ,  Salman R Punekar  6 ,  Alexander I Spira  7 ,  Ignacio Garrido-Laguna  8 ,  David S Hong  9 ,  Arvin C Dar  10 ,  Rona Yaeger  11 ,  Kathryn C Arbour  11 ,  Piro Lito  12
Affiliations
  • 1. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 2. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 3. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Tri-Institutional MD-PhD Program, Weill Cornell Medical College, Rockefeller University, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 4. Revolution Medicines, Redwood City, CA, USA.
  • 5. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 6. Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA.
  • 7. Virginia Cancer Specialists Research Institute, Fairfax, VA, USA.
  • 8. Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
  • 9. Department of Investigational Cancer Therapeutics, MD Anderson Cancer Center, Houston, TX, USA.
  • 10. Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 11. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
  • 12. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Tri-Institutional MD-PhD Program, Weill Cornell Medical College, Rockefeller University, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA. Electronic address: [email protected].
PMID: 42092352 DOI: 10.1016/j.cell.2026.03.031
Abstract

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.

Keywords
RAF; RAS; RAS inhibitor; acquired resistance; cancer; clinical resistance; daraxonrasib; molecular glues; targeted therapy; tri-complex inhibitor.
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