A plastic EMP1⁺ to LGR5⁺ cell state conversion as a bypass to KRAS-G12D pharmacological inhibition in metastatic colorectal cancer

  • Cancer Discov. 2025 Oct 21. doi: 10.1158/2159-8290.CD-25-0679.
Alessia Centonze  1 ,  Adrià-Jaume Roura  1 ,  Meritxell Novillo-Font  2 ,  Cristina Giordano  1 ,  Xavier Hernando-Momblona  1 ,  Montserrat Llanses  1 ,  Paula Prats  1 ,  Marta Sevillano  3 ,  Débora Cabot  4 ,  Mireia Novell  5 ,  Gabriel Pabst  6 ,  Florian Andersch  6 ,  Adrià Cañellas-Socias  1 ,  Chong Zhang  7 ,  Nikolaos-Nikiforos Giakoumakis  1 ,  Hugh Sparks  8 ,  Chris Dunsby  9 ,  Julien Colombelli  10 ,  Asunción Fernández-Barral  11 ,  Elena Sancho  10 ,  Camille Stephan-Otto Attolini  12 ,  Alberto Muñoz  13 ,  Antonio Barbachano  13 ,  Héctor G Palmer  4 ,  Jordi Martínez-Quintanilla  4 ,  Johannes Zuber  6 ,  Cristina Blaj  14 ,  Elsa Quintana  14 ,  Carme Cortina  1 ,  Marc A Marti-Renom  15 ,  Eduard Batlle  1
Affiliations
  • 1. Institute for Research in Biomedicine, Barcelona, Spain.
  • 2. Centre for Genomic Regulation, Barcelona, Spain.
  • 3. Institute for Research in Biomedicine, BARCELONA, BARCELONA, Spain.
  • 4. Vall d'Hebron Institute of Oncology, Barcelona, Spain.
  • 5. Centro Nacional de Análisis Genómico, Barcelona, Spain.
  • 6. Research Institute of Molecular Pathology, Vienna, Austria.
  • 7. Institute for Research in Biomedicine, United Kingdom.
  • 8. Imperial College London, London, Spain.
  • 9. Imperial College London, London, United Kingdom.
  • 10. Institute for Research in Biomedicine, Spain.
  • 11. Centro de Investigación Biomédica en Red de Cáncer, Spain.
  • 12. Institute for Research in Biomedicine, Barcelona, Barcelona, Spain.
  • 13. Centro de Investigación Biomédica en Red de Cáncer, Madrid, Spain.
  • 14. Revolution Medicines (United States), Redwood City, CA, United States.
  • 15. Centre for Genomic Regulation, Spain.
PMID: 41128661 DOI: 10.1158/2159-8290.CD-25-0679
Abstract

Inhibitors of the oncogene KRAS hold promise for treating metastatic CRC (mCRC). Here we show that a selective, covalent small molecule inhibitor of the active (ON) conformation of RAS-G12D, RMC-9945, exerts durable disease control in preclinical CRC models of early liver metastasis, but its therapeutic activity was diminished in the advanced metastatic disease. RMC-9945-treated metastases underwent a transition from a poor-prognosis-associated Emp1⁺ transcriptional state to a WNT-driven Lgr5⁺ stem cell-like state that withstands the absence of RAS-G12D activity. This cell state change occurred within hours of Ras(ON) inhibitor treatment through a shift in transcription factor usage that involved limited chromatin remodeling. Forced conversion of metastatic cells to the Lgr5⁺ state through RAS-G12D inhibition, followed by genetic ablation of this population, reduced metastatic burden and prolonged survival in a mouse mCRC model. Overall, these preclinical findings demonstrate a central role for oncogenic KRAS in governing cellular plasticity in mCRC.

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