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

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

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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