A Plastic EMP1+ to LGR5+ Cell State Conversion as a Bypass to KRASG12D Pharmacologic Inhibition in Metastatic Colorectal Cancer
We show that inhibition of oncogenic KRAS in preclinical models of advanced mCRC exerts a limited benefit, primarily due to the reversion of tumor cells to a stem cell-like state. Our findings highlight the context-dependent effects of oncogenic KRAS mutations and underscore cell plasticity as a therapeutic opportunity. See related commentary by Eng and Yilmaz et al., p. 201.
Authors
- Alberto Múñoz (ORCID: https://orcid.org/0000-0003-3890-4251)
- Julien Colombelli (ORCID: https://orcid.org/0000-0002-2784-4276)
- Montserrat Llanses Martinez (ORCID: https://orcid.org/0000-0002-5600-9181)
- Carme Cortina (ORCID: https://orcid.org/0000-0003-3477-4322)
- Antonio Barbáchano (ORCID: https://orcid.org/0000-0002-1248-5143)
- Elsa Quintana (ORCID: https://orcid.org/0000-0002-4123-1695)
- Hugh Sparks (ORCID: https://orcid.org/0000-0001-9900-6610)
- Pedro A Prats (ORCID: https://orcid.org/0009-0008-3235-0394)
- Débora Cabot
- Chong Zhang (ORCID: https://orcid.org/0000-0003-0679-7623)
- Gabriel Pabst (ORCID: https://orcid.org/0000-0003-1346-6398)
- Jordi Martínez‐Quintanilla (ORCID: https://orcid.org/0000-0003-4279-2926)
- Marta Sevillano (ORCID: https://orcid.org/0000-0001-5761-0879)
- Elena Sancho (ORCID: https://orcid.org/0000-0002-8182-513X)
- Adrià-Jaume Roura (ORCID: https://orcid.org/0000-0002-8271-8803)
- Florian Andersch (ORCID: https://orcid.org/0000-0001-6847-3355)
- Alessia Centonze (ORCID: https://orcid.org/0000-0002-4269-1933)
- Nickolaos Nikiforos Giakoumakis (ORCID: https://orcid.org/0000-0002-5280-3222)
- Cristina Blaj (ORCID: https://orcid.org/0000-0003-0449-2690)
- Eduard Batlle (ORCID: https://orcid.org/0000-0003-2422-0326)
- Adrià Cañellas‐Socias (ORCID: https://orcid.org/0000-0002-8373-7803)
- Marc A. Martı́-Renom (ORCID: https://orcid.org/0000-0002-0151-4279)
- Christopher Dunsby (ORCID: https://orcid.org/0000-0001-8782-0885)
- Camille Stephan‐Otto Attolini (ORCID: https://orcid.org/0000-0001-8045-320X)
- Asunción Fernández‐Barral (ORCID: https://orcid.org/0000-0002-1278-4645)
- Xavier Hernando‐Momblona (ORCID: https://orcid.org/0000-0003-0755-333X)
- Johannes Zuber (ORCID: https://orcid.org/0000-0001-8810-6835)
- Héctor G. Pálmer (ORCID: https://orcid.org/0000-0002-9823-5638)
- Cerrene N. Giordano
- Mireia Novell (ORCID: https://orcid.org/0009-0001-9043-8334)
- Meritxell Novillo-Font (ORCID: https://orcid.org/0000-0001-5352-5896)
Institutions
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Research Institute of Molecular Pathology (AT)
- Hospital Universitario La Paz (ES)
- The Francis Crick Institute (GB)
- Instituto de Investigaciones Biomédicas Sols-Morreale (ES)
- Revolution Medicines (United States) (US)
- Hospital La Paz Institute for Health Research (ES)
- NIHR Imperial Biomedical Research Centre (GB)
- Institute for Biomedicine (IT)
- Institute for Research in Biomedicine (ES)
- Vall d'Hebron Hospital Universitari (ES)
- Barcelona Institute of Science and Technology (ES)
- Centre for Genomic Regulation (ES)
- Centro Nacional de Análisis Genómico (ES)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Vall d'Hebron Institute of Oncology (ES)
- Imperial College London (GB)
- Universidad Autónoma de Madrid (ES)
Publication Details
- Journal
- Cancer Discovery
- Published
- 2025-10-21
- DOI
- https://doi.org/10.1158/2159-8290.cd-25-0679
- Citations
- 5
- Primary Topic
- Colorectal Cancer Treatments and Studies
- Type
- article
- Field-Weighted Citation Impact
- 5.23
Funders
- Institute for Research in Biomedicine
- “la Caixa” Foundation
- Revolution Medicines
- Cancer Research UK
- Generalitat de Catalunya
- Ministerio de Ciencia e Innovación
- Centro de Investigación Biomédica en Red de Cáncer